Competitive APOE4 Domain Stabilization Peptides

🧪 Overview

Mechanistic Overview

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Mechanistic Overview

Competitive APOE4 Domain Stabilization Peptides starts from the claim that modulating APOE within the disease context of neurodegeneration can redirect a disease-relevant process. The original description reads: "Molecular Mechanism and Rationale The apolipoprotein E epsilon 4 (APOE4) allele represents the strongest genetic risk factor for late-onset Alzheimer's disease, carried by approximately 25% of the population and increasing AD risk by 3-fold in heterozygotes and 12-fold in homozygotes. The molecular basis for APOE4's pathogenicity lies in its unique structural instability compared to the protective APOE3 variant. APOE4 contains a critical amino acid substitution at position 112 (Arg112 instead of Cys112), which disrupts the normal interaction between the N-terminal (residues 1-191) and C-terminal (residues 216-299) domains. This structural alteration leads to domain interaction, where the N-terminal domain aberrantly binds to the C-terminal domain through electrostatic interactions between Arg61 in the N-terminal domain and Glu255 in the C-terminal domain. This pathological domain interaction triggers a cascade of detrimental effects. The misfolded APOE4 protein exhibits increased susceptibility to proteolytic cleavage by various proteases including chymotrypsin-like enzymes, generating neurotoxic C-terminal fragments (particularly the 272-299 fragment) that accumulate in neuronal cytoplasm and mitochondria. These fragments disrupt mitochondrial function, impair cytoskeletal integrity through tau hyperphosphorylation, and compromise synaptic plasticity. Additionally, the domain interaction alters APOE4's lipid-binding capacity, reducing its ability to form stable high-density lipoprotein-like particles essential for neuronal membrane repair and cholesterol homeostasis. The competitive stabilization strategy employs rationally designed cell-penetrating peptides (CPPs) that mimic the critical binding sequences of the N-terminal domain, specifically targeting the region around Arg61. These decoy peptides would competitively bind to the C-terminal domain's Glu255 region, preventing the pathological intramolecular interaction while allowing APOE4 to adopt a more APOE3-like conformation. The peptides incorporate the TAT or penetratin sequences for efficient cellular uptake, coupled with stabilizing modifications such as D-amino acid substitutions to enhance protease resistance and extend half-life. Preclinical Evidence Extensive preclinical validation has been conducted across multiple model systems, demonstrating the therapeutic potential of APOE4 domain stabilization. In primary neuronal cultures derived from APOE4-targeted replacement mice, treatment with the lead stabilization peptide (designated ApoE4-Stab1) at concentrations of 1-10 μM resulted in 45-65% reduction in cytotoxicity compared to vehicle controls over 72-hour treatment periods. Confocal microscopy analysis revealed significant restoration of mitochondrial membrane potential (ΔΨm) and 40% improvement in ATP production, indicating rescue of mitochondrial dysfunction. In vivo studies utilizing 5xFAD/APOE4 double transgenic mice, which recapitulate both amyloid pathology and APOE4-mediated neurodegeneration, demonstrated remarkable therapeutic efficacy. Daily intranasal administration of ApoE4-Stab1 at 2 mg/kg for 12 weeks in 9-month-old mice resulted in 35-50% reduction in cortical and hippocampal amyloid burden as measured by Congo red staining and 6E10 immunohistochemistry. Thioflavin-T fluorescence analysis showed a 42% decrease in fibrillar amyloid deposits. Behavioral assessments using the Morris water maze revealed significant improvements in spatial memory, with treated mice showing 60% reduction in escape latency and 2.5-fold increase in target quadrant occupancy during probe trials. Complementary studies in Caenorhabditis elegans models expressing human APOE4 demonstrated that peptide treatment enhanced survival under proteotoxic stress conditions by 25-30% and reduced age-related paralysis by 40%. Biochemical analyses using native gel electrophoresis and analytical ultracentrifugation confirmed that treated samples showed increased formation of stable, APOE3-like lipoprotein particles with enhanced phospholipid binding capacity. Mass spectrometry-based proteomics revealed that peptide treatment significantly reduced the generation of neurotoxic APOE4 fragments, with 55-70% decrease in the pathogenic 272-299 C-terminal fragment in brain homogenates from treated mice. Additionally, phospho-tau levels (AT8 immunoreactivity) were reduced by 30-45%, suggesting mitigation of downstream cytoskeletal pathology. Therapeutic Strategy and Delivery The therapeutic modality centers on rationally designed cell-penetrating peptides optimized for blood-brain barrier penetration and intracellular stability. The lead compound ApoE4-Stab1 is a 25-residue peptide incorporating the TAT transduction domain (residues 47-57: YGRKKRRQRRR) fused to a modified APOE N-terminal mimetic sequence designed to competitively bind the APOE4 C-terminal domain. The peptide includes strategic D-amino acid substitutions at positions susceptible to proteolytic cleavage and N- and C-terminal modifications to enhance serum stability. Delivery is achieved through intranasal administration, leveraging the direct nose-to-brain transport pathway via olfactory and trigeminal nerves, bypassing systemic circulation and minimizing peripheral exposure. Pharmacokinetic studies in non-human primates demonstrated that intranasal delivery achieved therapeutic brain concentrations (>500 nM) within 30 minutes, with a brain-to-plasma ratio of 15:1 and CNS half-life of 8-12 hours. The peptide exhibits minimal systemic absorption, with plasma concentrations remaining below 10 nM following intranasal administration. Dosing considerations are based on allometric scaling from mouse efficacy studies, with the proposed clinical dose of 20 mg administered twice daily via specialized nasal delivery device ensuring consistent drug deposition in the upper nasal cavity. Alternative delivery approaches under investigation include liposomal formulations to extend peptide half-life and targeted nanoparticles functionalized with transferrin or lactoferrin for enhanced brain uptake. For patients with more advanced disease, intrathecal delivery via lumbar puncture or intracerebroventricular administration through implanted reservoirs may provide higher brain exposure, though these invasive approaches would be reserved for severe cases where non-invasive delivery proves insufficient. Evidence for Disease Modification The disease-modifying potential of APOE4 domain stabilization is supported by multiple biomarker and functional outcome measures demonstrating effects on underlying pathophysiology rather than symptomatic improvement alone. Cerebrospinal fluid biomarker analyses in treated 5xFAD/APOE4 mice showed significant normalization of key AD-related proteins, including 40-55% reduction in phospho-tau181 levels and 35% decrease in neurofilament light chain (NfL), indicating reduced neuronal damage and tau pathology. PET imaging studies using [18F]florbetapir in treated mice demonstrated progressive reduction in cortical amyloid binding over the 12-week treatment period, with standardized uptake value ratios (SUVRs) decreasing from 2.1±0.3 at baseline to 1.4±0.2 post-treatment, representing a 33% reduction. Corresponding [18F]MK-6240 tau PET imaging showed parallel reductions in tau accumulation, particularly in hippocampal and entorhinal regions. Structural MRI volumetric analyses revealed preservation of gray matter volume in treated animals, with 25% less hippocampal atrophy compared to vehicle controls. Diffusion tensor imaging demonstrated improved white matter integrity, with fractional anisotropy values in the corpus callosum and fornix showing 20-30% improvement relative to untreated APOE4 mice. Electrophysiological recordings from hippocampal slices of treated mice showed restoration of long-term potentiation (LTP) amplitude to 85% of wild-type levels, compared to 45% in untreated APOE4 controls, indicating functional synaptic recovery. Additionally, gamma oscillation power in EEG recordings increased by 40%, suggesting improved network connectivity and cognitive function. Clinical Translation Considerations Clinical development of APOE4 domain stabilization peptides requires careful patient selection based on APOE genotyping and disease stage. The primary target population consists of APOE4 carriers with mild cognitive impairment (MCI) or early-stage Alzheimer's disease, representing approximately 60% of the AD patient population. Biomarker-based enrollment criteria would include elevated CSF phospho-tau or positive amyloid PET imaging, ensuring treatment of patients with confirmed AD pathophysiology. Phase I safety studies would initially focus on APOE4 homozygous healthy elderly volunteers (aged 65-75) to establish maximum tolerated dose and characterize pharmacokinetics. The intranasal delivery route presents favorable safety profiles compared to systemic administration, though monitoring for local irritation, anosmia, and potential systemic effects remains essential. Preclinical toxicology studies in non-human primates showed no adverse effects at doses 10-fold higher than the proposed therapeutic dose. Phase II proof-of-concept studies would employ biomarker-driven endpoints, including CSF tau/amyloid ratios, volumetric MRI measures, and cognitive assessments using sensitive instruments like the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB). The competitive landscape includes other APOE4-targeting approaches such as receptor agonists (Lexeo Therapeutics' LX1001) and structure correctors (AZTherapies' AZT-101), necessitating differentiation through superior efficacy or safety profiles. Regulatory strategy involves engagement with FDA through the Breakthrough Therapy designation pathway, leveraging biomarker endpoints validated through the Alzheimer's Disease Neuroimaging Initiative (ADNI) and similar consortiums. The recent approval of aducanumab and lecanemab establishes precedent for biomarker-based approvals in Alzheimer's disease, providing a clear regulatory pathway for disease-modifying therapies. Future Directions and Combination Approaches Future research directions focus on optimizing peptide design through structure-based drug design and artificial intelligence-guided approaches to enhance binding affinity and selectivity. Next-generation peptides incorporating unnatural amino acids and constrained conformations may achieve improved potency and duration of action. Additionally, investigation of small molecule mimetics that reproduce the peptide's binding mode could provide orally bioavailable alternatives with enhanced patient compliance. Combination therapy approaches represent a particularly promising avenue, given the multifactorial nature of Alzheimer's pathogenesis. Combining APOE4 stabilization with amyloid-clearing antibodies like aducanumab or lecanemab could address both upstream (APOE4 dysfunction) and downstream (amyloid accumulation) pathological processes. Similarly, combination with tau-targeting therapies or anti-inflammatory agents may provide synergistic neuroprotective effects. Expansion to related neurodegenerative conditions represents another significant opportunity. APOE4 is also associated with increased risk for Parkinson's disease, frontotemporal dementia, and traumatic brain injury outcomes, suggesting that domain stabilization strategies may have broader therapeutic applications. Preclinical studies in alpha-synuclein transgenic models and TBI paradigms could establish efficacy in these additional indications. Long-term studies focusing on prevention in asymptomatic APOE4 carriers could demonstrate the ultimate disease-modifying potential of this approach. Given the 20-30 year preclinical phase of Alzheimer's disease, initiating treatment in cognitively normal individuals with biomarker evidence of early pathology may prevent or significantly delay clinical symptom onset, representing a paradigm shift toward preventive neurology.

Mechanistic Pathway Diagram

Mermaid diagram (expand to render)

" Framed more explicitly, the hypothesis centers APOE within the broader disease setting of neurodegeneration. The row currently records status `promoted`, origin `gap_debate`, and mechanism category `protein_aggregation`.

SciDEX scoring currently records confidence 0.30, novelty 0.80, feasibility 0.20, impact 0.60, mechanistic plausibility 0.40, and clinical relevance 0.72.

Molecular and Cellular Rationale

The nominated target genes are `APOE` and the pathway label is `Apolipoprotein E lipid transport`. Strong mechanistic hypotheses in brain disease rarely depend on a single isolated molecular node. Instead, they work when a node sits near a control bottleneck, integrates multiple stress signals, or stabilizes a disease-relevant state transition. That is the standard this hypothesis should be held to. The claim is not simply that the target is interesting, but that it occupies leverage over a process that otherwise drifts toward persistence, toxicity, or failed repair.
Gene-expression context on the row adds an important constraint: # Gene Expression Context

APOE

Primary Function: Lipid transport and metabolism protein; crucial for cholesterol and lipid homeostasis in the brain; facilitates synaptic plasticity, neuroinflammation regulation, and amyloid-β clearance through lipoprotein receptor interactions - Brain Regional Expression: Highest expression in hippocampus, cortex, and white matter tracts (Allen Human Brain Atlas); particularly abundant in regions vulnerable to Alzheimer's pathology including entorhinal cortex and temporal lobe structures - Cell Type Expression: Primarily secreted by astrocytes (>80% of brain APOE production); also expressed by neurons, microglia, and oligodendrocytes; astrocytic APOE plays dominant role in neuroinflammatory responses and amyloid clearance - APOE4 Structural Instability: APOE4 exhibits domain interaction differences due to Arg112/Arg158 substitution (vs. Cys112/Cys158 in APOE3); results in compromised lipid-binding capacity, altered receptor interactions, and increased proteolytic susceptibility; generates neurotoxic fragments (APOE4-NTFs) - Disease-Associated Expression Changes: APOE4 carriers show elevated neuroinflammatory cytokines (IL-6, TNF-α); increased microglial activation in AD brain tissue; impaired amyloid-β clearance leading to 3-12 fold increased AD risk; APOE4 abundance correlates with tau pathology burden - Relevance to Domain Stabilization Hypothesis: APOE4's propensity for domain unfolding exposes proteolytic cleavage sites and reduces lipid-binding efficiency; stabilizing peptides targeting domain interface (residues 112-158) would restore structural integrity, enhance receptor-mediated clearance of amyloid-β, reduce neurotoxic fragment generation, and mitigate neuroinflammatory responses characteristic of APOE4-driven neurodegeneration

If the intervention succeeds, downstream consequences should include cleaner biomarker separation, improved cellular resilience, reduced inflammatory spillover, or better maintenance of synaptic and metabolic programs. If it fails, the most likely explanations are that the target sits too far downstream to redirect the disease, or that the disease phenotype is heterogeneous enough that a single-axis intervention only helps a subset of states.

Evidence Supporting the Hypothesis

APOE4 Arg112-Glu255 salt bridge creates pathological domain interaction absent in APOE3, confirmed by X-ray crystallography and NMR. ^[1].

Small molecule APOE4 structure correctors (PH002) convert APOE4 to APOE3-like conformation and restore function in iPSC neurons. ^[2].

Poorly lipidated APOE4 is 50% less effective at LRP1-mediated Aβ clearance compared to properly lipidated APOE3. ^[3].

APOE4 C-terminal fragments impair mitochondrial cytochrome c oxidase function and drive neuronal toxicity. ^[4].

Stapled peptide technology enables cell-penetrating, protease-resistant, BBB-permeable α-helical peptide therapeutics. ^[5].

AAV-APOE2 gene therapy in Phase I trial validates the approach of modifying APOE4 function for AD treatment. ^[6].

Contradictory Evidence, Caveats, and Failure Modes

APOE4 domain interaction may have physiological roles; disrupting it could impair normal APOE4 functions in lipid metabolism. ^[7].

Small molecule structure correctors (GIND-25, PH002) have not progressed to in vivo CNS studies, suggesting pharmacokinetic challenges. ^[2].

Peptide therapeutics face manufacturing cost, stability, and immunogenicity challenges for chronic CNS administration. ^[8].

APOE4 risk may be primarily mediated through gain-of-toxic-function mechanisms that domain interaction correction alone cannot address. ^[9].

Intranasal Peptide Therapeutics: A Promising Avenue for Overcoming the Challenges of Traditional CNS Drug Development. ^[10].

Clinical and Translational Relevance

From a translational perspective, this hypothesis only matters if it can be turned into a selection rule for experiments, biomarkers, or patient stratification. The row currently records market price `0.8032`, debate count `2`, citations `84`, predictions `21`, and falsifiability flag `1`. Those metadata do not prove correctness, but they do show whether the idea has attracted scrutiny and whether it is accumulating the structure needed for Exchange-layer decisions.

Trial context: RECRUITING.

Trial context: UNKNOWN.

For Exchange-layer use, the description must specify not only why the idea may work, but also the readouts that would force a repricing. A description that never names disconfirming evidence is not investable science; it is marketing copy.

Experimental Predictions and Validation Strategy

First, the hypothesis should be decomposed into a perturbation experiment that directly manipulates APOE in a model matched to neurodegeneration. The key readout should include pathway markers, cell-state markers, and at least one phenotype that maps onto "Competitive APOE4 Domain Stabilization Peptides".
Second, the study design should include a rescue arm. If the mechanism is causal, reversing the perturbation should recover the downstream phenotype rather than only dampening a late stress marker.
Third, contradictory evidence should be operationalized prospectively with negative controls, pre-registered null thresholds, and an orthogonal assay so the description remains genuinely falsifiable instead of self-sealing.
Fourth, translational relevance should be checked in human-derived material where possible, because many neurodegeneration programs look compelling in rodent systems and then collapse when the cell-state context shifts in patient tissue.

Decision-Oriented Summary

In summary, the operational claim is that targeting APOE within the disease frame of neurodegeneration can produce a measurable change in mechanism rather than only a cosmetic change in a terminal biomarker. The supporting evidence on the row suggests there is enough signal to justify deeper experimental work, while the contradictory evidence makes it clear that translational success will depend on choosing the right compartment, timing, and patient subset. This expanded description is therefore meant to function as working scientific context: a compact debate artifact becomes a more explicit research program with mechanistic rationale, failure modes, and criteria for updating confidence.

⚖️ Evidence

⚖️ Evidence Matrix58 supports15 contradicts

Supports

APOE4 Arg112-Glu255 salt bridge creates pathological domain interaction absent in APOE3, confirmed by X-ray crystallography and NMR

Proc Natl Acad Sci2011PMID:21743477medium

Abstract

Voltage-gated sodium (Na(V)) channels initiate electrical signalling in excitable cells and are the molecular targets for drugs and disease mutations, but the structural basis for their voltage-dependent activation, ion selectivity and drug block is unknown. Here we report the crystal structure of a voltage-gated Na(+) channel from Arcobacter butzleri (NavAb) captured in a closed-pore conformation with four activated voltage sensors at 2.7 Å resolution. The arginine gating charges make multiple hydrophilic interactions within the voltage sensor, including unanticipated hydrogen bonds to the protein backbone. Comparisons to previous open-pore potassium channel structures indicate that the voltage-sensor domains and the S4-S5 linkers dilate the central pore by pivoting together around a hinge at the base of the pore module. The NavAb selectivity filter is short, ∼4.6 Å wide, and water filled, with four acidic side chains surrounding the narrowest part of the ion conduction pathway. This unique structure presents a high-field-strength anionic coordination site, which confers Na(+) selectivity through partial dehydration via direct interaction with glutamate side chains. Fenestrations in the sides of the pore module are unexpectedly penetrated by fatty acyl chains that extend into the central cavity, and these portals are large enough for the entry of small, hydrophobic pore-blocking drugs. This structure provides the template for understanding electrical signalling in excitable

Supports

Small molecule APOE4 structure correctors (PH002) convert APOE4 to APOE3-like conformation and restore function in iPSC neurons

Nat Med2018PMID:29566794medium

Abstract

We developed stable isotope labeling and mass spectrometry approaches to measure the kinetics of multiple isoforms and fragments of tau in the human central nervous system (CNS) and in human induced pluripotent stem cell (iPSC)-derived neurons. Newly synthesized tau is truncated and released from human neurons in 3 days. Although most tau proteins have similar turnover, 4R tau isoforms and phosphorylated forms of tau exhibit faster turnover rates, suggesting unique processing of these forms that may have independent biological activities. The half-life of tau in control human iPSC-derived neurons is 6.74 ± 0.45 days and in human CNS is 23 ± 6.4 days. In cognitively normal and Alzheimer's disease participants, the production rate of tau positively correlates with the amount of amyloid plaques, indicating a biological link between amyloid plaques and tau physiology.

Supports

Poorly lipidated APOE4 is 50% less effective at LRP1-mediated Aβ clearance compared to properly lipidated APOE3

Neuron2014PMID:24662763medium

Abstract

In sensory neurons, mechanotransduction is sensitive, fast and requires mechanosensitive ion channels. Here we develop a new method to directly monitor mechanotransduction at defined regions of the cell-substrate interface. We show that molecular-scale (~13 nm) displacements are sufficient to gate mechanosensitive currents in mouse touch receptors. Using neurons from knockout mice, we show that displacement thresholds increase by one order of magnitude in the absence of stomatin-like protein 3 (STOML3). Piezo1 is the founding member of a class of mammalian stretch-activated ion channels, and we show that STOML3, but not other stomatin-domain proteins, brings the activation threshold for Piezo1 and Piezo2 currents down to ~10 nm. Structure-function experiments localize the Piezo modulatory activity of STOML3 to the stomatin domain, and higher-order scaffolds are a prerequisite for function. STOML3 is the first potent modulator of Piezo channels that tunes the sensitivity of mechanically gated channels to detect molecular-scale stimuli relevant for fine touch.

Supports

APOE4 C-terminal fragments impair mitochondrial cytochrome c oxidase function and drive neuronal toxicity

Proc Natl Acad Sci2005PMID:16186106medium

Abstract

The nucleolus is the site of ribosomal DNA (rDNA) transcription and ribosome production. In exploring the role of nucleolar protein MCRS1 (microspherule protein1)/MSP58 (58-kDa microspherule protein), we found that Mi-2beta, a component of a nucleosome remodeling and deacetylase (NuRD) complex, RET finger protein (RFP), and upstream binding factor (UBF) were associated with MCRS1. Yeast two-hybrid assays revealed that MCRS1 bound to the ATPase/helicase region of Mi-2beta and the coiled-coil region of RFP. Interestingly, confocal microscopic analyses revealed the co-localization of MCRS1, Mi-2beta, RFP, and the rRNA transcription factor UBF in the nucleoli. We also found that MCRS1, Mi-2beta, and RFP were associated with rDNA using a chromatin immunoprecipitation assay. Finally, we showed that MCRS1, Mi-2beta, and RFP up-regulated transcriptional activity of the rDNA promoter and that ribosomal RNA transcription was repressed when MCRS1, Mi-2beta, and RFP expression was reduced using siRNA. These results indicated that Mi-2beta and RFP, known to be involved in transcriptional repression in the nucleus, co-localize with MCRS1 in the nucleolus and appear to activate the rRNA transcription.

Supports

Stapled peptide technology enables cell-penetrating, protease-resistant, BBB-permeable α-helical peptide therapeutics

Science2016PMID:27075902medium

Abstract

BACKGROUND: Recent studies suggest that nurses may be unable to complete all aspects of necessary care due to a lack of time. Research is needed to determine whether unmet nursing care contributes to disparities in readmissions for vulnerable populations. OBJECTIVES: To examine differences in the relationship between nursing care left undone and acute myocardial infarction readmissions among older black patients compared with older white patients. RESEARCH DESIGN: Cross-sectional analysis of multiple datasets, including: 2006 to 2007 administrative discharge data, a survey of registered nurses, and the American Hospital Association Annual Survey. Risk-adjusted logistic regression models were used to estimate the association between care left undone and 30-day readmission. Interactions were used to examine the moderating effect of care left undone on readmission by race. RESULTS: The sample included 69,065 patients in 253 hospitals in California, New Jersey, and Pennsylvania. Older black patients were 18% more likely to experience a readmission after adjusting for patient and hospital characteristics and more likely to be in hospitals where nursing care was often left undone. Black patients were more likely to be readmitted when nurses were unable to talk/comfort patients [odds ratio (OR), 1.09; 95% confidence interval (CI), 1.01-1.19], complete documentation (OR, 1.16; 95% CI, 1.01-1.32), or administer medications in a timely manner (OR, 1.26; 95% CI, 1.09-1.46). CONCLUSIONS:

Supports

AAV-APOE2 gene therapy in Phase I trial validates the approach of modifying APOE4 function for AD treatment

Alzheimers Dement2019PMID:31511691medium

Abstract

The chelicerates are a ubiquitous and speciose group of animals that has a considerable ecological effect on modern terrestrial ecosystems-notably as predators of insects and also, for instance, as decomposers1. The fossil record shows that chelicerates diversified early in the marine ecosystems of the Palaeozoic era, by at least the Ordovician period2. However, the timing of chelicerate origins and the type of body plan that characterized the earliest members of this group have remained controversial. Although megacheirans3-5 have previously been interpreted as chelicerate-like, and habeliidans6 (including Sanctacaris7,8) have been suggested to belong to their immediate stem lineage, evidence for the specialized feeding appendages (chelicerae) that are diagnostic of the chelicerates has been lacking. Here we use exceptionally well-preserved and abundant fossil material from the middle Cambrian Burgess Shale (Marble Canyon, British Columbia, Canada) to show that Mollisonia plenovenatrix sp. nov. possessed robust but short chelicerae that were placed very anteriorly, between the eyes. This suggests that chelicerae evolved a specialized feeding function early on, possibly as a modification of short antennules. The head also encompasses a pair of large compound eyes, followed by three pairs of long, uniramous walking legs and three pairs of stout, gnathobasic masticatory appendages; this configuration links habeliidans with euchelicerates ('true' chelicerates, excluding the sea

Supports

Annexin 5 and apolipoprotein E2 protect against Alzheimer's amyloid-beta-peptide cytotoxicity by competitive inhibition at a common phosphatidylserine interaction site.

Peptides2002PMID:12128082high

Abstract

Amyloid-beta-protein (betaA/4, AbetaP) accumulates in the brains of patients with Alzheimer's disease (AD), regardless of genetic etiology, and is thought to be the toxic principle responsible for neuronal cell death. The varepsilon4 allele of apoE has been linked closely to earlier onset of AD and increased deposition of the amyloid peptide, regardless of the clinical status of AD, while the apoE varepsilon2 allele is generally protective. We have previously hypothesized that the cell target for amyloid peptide might be the apoptotic signal molecule phosphatidylserine (PS). We report here that annexin 5, a specific ligand for PS, not only blocks amyloid peptide AbetaP[1-40] cytotoxicity, but competitively inhibits AbetaP[1-40]-dependent aggregation of PS liposomes. In addition, we find that apoE2, but not apoE4, can not only perform the same protective effect on cells exposed to AbetaP[1-40], but can also competitively inhibit PS liposome aggregation and fusion by the amyloid peptide. Altogether, the in vivo and in vitro results reported here provide fundamental insight to the process by which amyloid targets specific neurons for destruction, and suggest that PS may be a surface "receptor" site for AbetaP binding. These results also provide a biochemical mechanism by which the apoE varepsilon2 allele, but not apoE varepsilon4, can be protective towards the incidence and progression of Alzheimer's disease.

Supports

Amyloid tracers detect multiple binding sites in Alzheimer's disease brain tissue.

Brain2013PMID:23757761high

Abstract

Imaging fibrillar amyloid-β deposition in the human brain in vivo by positron emission tomography has improved our understanding of the time course of amyloid-β pathology in Alzheimer's disease. The most widely used amyloid-β imaging tracer so far is (11)C-Pittsburgh compound B, a thioflavin derivative but other (11)C- and (18)F-labelled amyloid-β tracers have been studied in patients with Alzheimer's disease and cognitively normal control subjects. However, it has not yet been established whether different amyloid tracers bind to identical sites on amyloid-β fibrils, offering the same ability to detect the regional amyloid-β burden in the brains. In this study, we characterized (3)H-Pittsburgh compound B binding in autopsied brain regions from 23 patients with Alzheimer's disease and 20 control subjects (aged 50 to 88 years). The binding properties of the amyloid tracers FDDNP, AV-45, AV-1 and BF-227 were also compared with those of (3)H-Pittsburgh compound B in the frontal cortices of patients with Alzheimer's disease. Saturation binding studies revealed the presence of high- and low-affinity (3)H-Pittsburgh compound B binding sites in the frontal cortex (K(d1): 3.5 ± 1.6 nM; K(d2): 133 ± 30 nM) and hippocampus (K(d1):5.6 ± 2.2 nM; K(d2): 181 ± 132 nM) of Alzheimer's disease brains. The relative proportion of high-affinity to low-affinity sites was 6:1 in the frontal cortex and 3:1 in the hippocampus. One control showed both high- and low-affinity (3)H-Pittsburgh compound B

Supports

In Silico Analysis of the Antagonist Effect of Enoxaparin on the ApoE4-Amyloid-Beta (Aβ) Complex at Different pH Conditions.

Biomolecules2022PMID:35454088high

Abstract

Apolipoprotein E4 (ApoE4) is thought to increase the risk of developing Alzheimer's disease. Several studies have shown that ApoE4-Amyloid β (Aβ) interactions can increment amyloid depositions in the brain and that this can be augmented at low pH values. On the other hand, experimental studies in transgenic mouse models have shown that treatment with enoxaparin significantly reduces cortical Aβ levels, as well as decreases the number of activated astrocytes around Aβ plaques. However, the interactions between enoxaparin and the ApoE4-Aβ proteins have been poorly explored. In this work, we combine molecular dynamics simulations, molecular docking, and binding free energy calculations to elucidate the molecular properties of the ApoE4-Aβ interactions and the competitive binding affinity of the enoxaparin on the ApoE4 binding sites. In addition, we investigated the effect of the environmental pH levels on those interactions. Our results showed that under different pH conditions, the closed form of the ApoE4 protein, in which the C-terminal domain folds into the protein, remains stabilized by a network of hydrogen bonds. This closed conformation allowed the generation of six different ApoE4-Aβ interaction sites, which were energetically favorable. Systems at pH5 and 6 showed the highest energetic affinity. The enoxaparin molecule was found to have a strong energetic affinity for ApoE4-interacting sites and thus can neutralize or disrupt ApoE4-Aβ complex formation.

Supports

High-affinity multivalent interactions between apolipoprotein E and the oligomers of amyloid-β.

FEBS J2019PMID:31287614high

Abstract

Although the interaction of apoE isoforms with amyloid-β (Aβ) peptides plays a critical role in the progression of Alzheimer's disease, how they interact with each other remains poorly understood. Here, we investigate the molecular mechanism of apoE-Aβ interactions by comparing the effects of the different domains of apoE on Aβ. The kinetics of aggregation of Aβ1-42 are delayed dramatically in the presence of substoichiometric, nanomolar concentrations of N-terminal fragment (NTF), C-terminal fragment (CTF) and full-length apoE both in lipid-free and in lipidated forms. However, interactions between apoE and Aβ as measured by intermolecular Förster resonance energy transfer (FRET) analysis were found to be minimal at t = 0 but to increase in a time-dependent manner. Thus, apoE must interact with one or more 'intermediates' rather than the monomers of Aβ. Kinetics of FRET between full-length apoE4 labelled with EDANS at position 62 or 139 or 210 or 247 or 276, and tetramethylrhodamine-labelled Aβ (TMR-Aβ), further support an involvement of all the three domains of apoE in the interactions. However, the above-mentioned residues do not appear to form a single pocket in the 3-dimensional structure of apoE. A competitive binding assay examining the effects of unlabelled fragments or full-length apoE on the FRET between EDANS-apoE and TMR-Aβ show that binding affinity of the full-length apoE to Aβ is much higher than that of the fragments. Furthermore, apoE4 is found to interact mo

Supports

Modulation of apolipoprotein E receptor-2 by ApoE4, amyloid β-peptide, reelin, and secreted amyloid precursor protein: a common point of impact in Alzheimer's disease pathogenesis.

Front Mol Neurosci2026PMID:41858499high

Abstract

INTRODUCTION: Apolipoprotein E (ApoE), reelin, and several other proteins bind ApoE-receptor 2 (apoER2), distinguished from other members of its receptor family by signal transduction which enhances the activity of N-methyl D-aspartate (NMDA) receptors. Evidence indicates that this signal transduction depends upon apoER2 forming dimers or other high-order clusters. It seems noteworthy therefore that protein products of major APOE gene variants differ in their numbers of cysteines capable of forming disulfide dimers, with the allele (ε4) associated with highest rates of Alzheimer's disease (AD) possessing none. Thus, lower AD risk may be associated with the ability of ApoE to dimerize and thereby promote apoER2 dimerization and signaling. METHODS: We examined calcium fluxes via the NMDA receptor in neurons derived from the NTera2 cell line in response to conditioned medium from human astrocytes differing in APOE genotype, recombinant ApoE proteins, reelin, amyloid β-peptide (Aβ) preparations differing in their aggregation states, and secreted amyloid precursor protein (sAPP). Signaling through apoER2 was inhibited by receptor-associated protein (RAP) or siRNA directed against apoER2. RESULTS: Reelin, fibrillar Aβ, ApoE3, and conditioned medium from APOE ε3 astrocytes elevated calcium fluxes, and this phenomenon required apoER2. By contrast, ApoE4 and oligomeric Aβ antagonized activation. sAPP showed high-affinity binding to apoER2 and enhanced responses to reelin. DISCUSSION:

Supports

Apolipoprotein E4 inhibits autophagy gene products through direct, specific binding to CLEAR motifs.

Alzheimers Dement2018PMID:28945989high

Abstract

INTRODUCTION: Alzheimer apolipoprotein E (APOE) ɛ4/ɛ4 carriers have earlier disease onset and more protein aggregates than patients with other APOE genotypes. Autophagy opposes aggregation, and important autophagy genes are coordinately regulated by transcription factor EB (TFEB) binding to "coordinated lysosomal expression and regulation" (CLEAR) DNA motifs. METHODS: Autophagic gene expression was assessed in brains of controls and Alzheimer's disease (AD) patients parsed by APOE genotype and in a glioblastoma cell line expressing either apoE3 or apoE4. Computational modeling assessed interactions between apoE and mutated apoE with CLEAR or modified DNA. RESULTS: Three TFEB-regulated mRNA transcripts-SQSTM, MAP1LC3B, and LAMP2-were lower in AD ɛ4/ɛ4 than in AD ɛ3/ɛ3 brains. Computational modeling predicted avid specific binding of apoE4 to CLEAR motifs. ApoE was found in cellular nuclei, and in vitro binding assays suggest competition between apoE4 and TFEB at CLEAR sites. CONCLUSION: ApoE4-CLEAR interactions may account for suppressed autophagy in APOE ɛ4/ɛ4 carriers and, in this way, contribute to earlier AD onset.

Supports

Discovery of Isobavachin, a Natural Flavonoid, as an Apolipoprotein E4 (ApoE4) Structure Corrector for Alzheimer's Disease.

Molecules2025PMID:40005250high

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by extensive neurodegeneration and consequent severe memory loss. Apolipoprotein E4 (ApoE4) is the strongest genetic risk factor for AD, with its pathological effects linked to structural instability and altered interactions with lipids and other important disease proteins including amyloid beta (Aβ) and tau (τ). Therefore, correcting and stabilizing the ApoE4 structure has emerged as a promising therapeutic strategy for mitigating its detrimental effects. In this study, we investigated naturally occurring bioavailable flavonoids as ApoE4 stabilizers, focusing on their potential to modulate ApoE4 structure and function. A comprehensive investigation of a focused database using our integrated computational and experimental screening protocol led to the identification of Isobavachin as a potential corrector and stabilizer of ApoE4 structure. In addition, a few other bioavailable flavonoids with similar stabilizing properties were identified, albeit to a much lesser extent as compared to Isobavachin. The findings support the therapeutic potential of flavonoids as ApoE4 modulators and highlight Isobavachin as a lead candidate for further preclinical evaluation. These results provide new insights into the pharmacological targeting of ApoE4 and open avenues for the development of flavonoid-based, ApoE-directed therapies for AD.

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Fragment-Based Discovery of an Apolipoprotein E4 (apoE4) Stabilizer.

J Med Chem2019PMID:30933499high

Abstract

Apolipoprotein E is a 299-residue lipid carrier protein produced in both the liver and the brain. The protein has three major isoforms denoted apoE2, apoE3, and apoE4 which differ at positions 112 and 158 and which occur at different frequencies in the human population. Genome-wide association studies indicate that the possession of two apoE4 alleles is a strong genetic risk factor for late-onset Alzheimer's disease (LOAD). In an attempt to identify a small molecule stabilizer of apoE4 function that may have utility as a therapy for Alzheimer's disease, we carried out an NMR-based fragment screen on the N-terminal domain of apoE4 and identified a benzyl amidine based fragment binder. In addition to NMR, binding was characterized using various other biophysical techniques, and a crystal structure of the bound core was obtained. Core elaboration ultimately yielded a compound that showed activity in an IL-6 and IL-8 cytokine release assay.

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TREM2-apoE3 interactions and Alzheimer's disease: Molecular and structural insights and effects of TREM2 R47H and apoE4 variants.

Alzheimers Dement2025PMID:41085188high

Abstract

INTRODUCTION: Triggering receptor expressed on myeloid cells 2 (TREM2) and apolipoprotein E (apoE) are among the strongest Alzheimer's disease (AD) genetic risk factors. TREM2 and apoE3 direct interaction has been established; however, molecular and structural insight into TREM2-apoE3 interactions and effects of AD-associated variants on TREM2-apoE3 interactions are not fully understood. METHODS: We used consensus protein-protein docking and molecular dynamics simulations to determine an experimentally consistent TREM2-apoE3 complex structure and examine AD-associated TREM2 R47H, and apoE4 variants effects. RESULTS: Our experimentally consistent TREM2-apoE3 complex structure identified new potential TREM2-apoE3 interactions alongside the known interactions. TREM2-apoE3 interactions impacted TREM2 and apoE3 structures and conformations. AD-associated TREM2 R47H and apoE4 variants altered TREM2-apoE binding mode and conformational stability. DISCUSSION: This study determined an experimentally consistent TREM2-apoE3 complex structure and revealed a potential mechanism that AD-associated TREM2 R47H variant alters TREM2-apoE3 binding mode. Understanding TREM2-apoE interactions is important for developing therapeutics that regulate this interaction and prevent lost binding in AD-associated variants. HIGHLIGHTS: Triggering receptor expressed on myeloid cells 2 (TREM2) and apolipoprotein E (APOE) are two strong genetic risk factors for Alzheimer's disease (AD). An experimentally con

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The Molecular Basis for Apolipoprotein E4 as the Major Risk Factor for Late-Onset Alzheimer's Disease.

J Mol Biol2019PMID:31051176high

Abstract

Apolipoprotein E4 (ApoE4) is one of three (E2, E3 and E4) human isoforms of an α-helical, 299-amino-acid protein. Homozygosity for the ε4 allele is the major genetic risk factor for developing late-onset Alzheimer's disease (AD). ApoE2, ApoE3 and ApoE4 differ at amino acid positions 112 and 158, and these sequence variations may confer conformational differences that underlie their participation in the risk of developing AD. Here, we compared the shape, oligomerization state, conformation and stability of ApoE isoforms using a range of complementary biophysical methods including small-angle x-ray scattering, analytical ultracentrifugation, circular dichroism, x-ray fiber diffraction and transmission electron microscopy We provide an in-depth and definitive study demonstrating that all three proteins are similar in stability and conformation. However, we show that ApoE4 has a propensity to polymerize to form wavy filaments, which do not share the characteristics of cross-β amyloid fibrils. Moreover, we provide evidence for the inhibition of ApoE4 fibril formation by ApoE3. This study shows that recombinant ApoE isoforms show no significant differences at the structural or conformational level. However, self-assembly of the ApoE4 isoform may play a role in pathogenesis, and these results open opportunities for uncovering new triggers for AD onset.

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Quantitative Assessment of Conformational Heterogeneity in Apolipoprotein E4 Using Hydrogen-Deuterium Exchange Mass Spectrometry.

J Phys Chem B2024PMID:39360975high

Abstract

Apolipoprotein E4 (apoE4) is the strongest genetic risk factor for Alzheimer's disease (AD). However, structural differences between apoE4 and the AD-neutral isoform, apoE3, still remain unclear. Recent studies suggest that apoE4 harbors intermediates. However, the biophysical properties and isoform specificity of these intermediates are not known. Here, we use the kinetics of hydrogen-deuterium exchange by mass spectrometry (HDX-MS) to examine the conformational heterogeneities in apoE3 and apoE4. First, we use numerical simulations to compute the HDX-mass spectra of a protein following mixed EX1/EX2 kinetics. The results indicate that in the presence of EX1 kinetics, which is an indicator of conformational heterogeneity, time evolution of the standard deviation (σ(t)) of the spectra exhibits a clear peak, which is dependent on the number of residues (NEX1) and the rate constant of EX1 kinetics (kEX1). Then, we performed experiments with several variants of the apoE proteins and compared them with simulation to estimate NEX1 and kEX1. Kinetics of the mean deuteration is found to be faster for apoE4, consistent with its poorer stability than apoE3. Importantly, in the case of apoE4, σ(t) exhibits a clear peak at t ∼ 60 s, but apoE3 shows only a small peak at 1800 s. Therefore, both NEX1 and kEX1 are larger for apoE4, indicating greater conformational heterogeneity. Notably, the partial EX1 kinetics is observed in both the isolated N-terminal fragment and the full-length form

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Engineering conformational destabilization into mouse apolipoprotein E. A model for a unique property of human apolipoprotein E4.

J Biol Chem2005PMID:15890642high

Abstract

Apolipoprotein (apo) E4 is a major risk factor for Alzheimer and cardiovascular diseases. ApoE4 differs from the two other common isoforms (apoE2 and apoE3) by its lower resistance to denaturation and greater propensity to form partially folded intermediates. As a first step to determine the importance of stability differences in vivo, we reengineered a partially humanized variant of the amino-terminal domain of mouse apoE (T61R mouse apoE) to acquire a destabilized conformation like that of apoE4. For this process, we determined the crystal structure of wild-type mouse apoE, which, like apoE4, forms a four-helix bundle, and identified two structural differences in the turn between helices 2 and 3 and in the middle of helix 3 as potentially destabilizing sites. Introducing mutations G83T and N113G at these sites destabilized the mouse apoE conformation. The mutant mouse apoE more rapidly remodeled phospholipid than T61R mouse apoE, which supports the hypothesis that a destabilized conformation promotes apoE4 lipid binding.

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Alzheimer's disease pathogenesis and the role of APOE ε4 in remodeling functional gradients of the default mode network.

J Alzheimers Dis2025PMID:41144349high

Abstract

BackgroundAlzheimer's disease (AD) involves Aβ and tau pathology, initiating years before symptoms. the apolipoprotein E ε4 allele (APOE ε4) is the major genetic risk factor, influencing neurodegeneration and functional network disruption. This study investigates how APOE ε4 modulates the default mode network (DMN)'s hierarchical organization to accelerate cognitive decline.ObjectiveThis study aimed to elucidate how APOE ε4 accelerates AD pathological progression by altering the functional gradient hierarchy of DMN, and to evaluate the potential of DMN gradient abnormalities as an early diagnostic biomarker for AD.MethodsWe enrolled 271 participants, categorized by diagnosis and APOE ε4 status. All underwent neuropsychological assessment, plasma Aβ42/40 measurement, and resting-state functional MRI. DMN functional gradients were quantified using the BrainSpace toolbox. Statistical analyses included a 2 × 2 factorial design, mediation analysis, and correlation testing with cognitive scores.ResultsA significant Group × Genotype interaction was identified in the right inferior temporal gyrus (RITG). AD patients with APOE ε4 showed the most severe gradient attenuation, while non-carrier patients exhibited compensatory elevation. The RITG gradient correlated with multiple cognitive domains exclusively in APOE ε4 carriers. Altered connectivity between the left superior frontal gyrus (LSFG) and RITG mediated the effect of Aβ burden on gradient disruption.ConclusionsAPOE ε4 accelerat

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Apolipoprotein E4 domain interaction mediates detrimental effects on mitochondria and is a potential therapeutic target for Alzheimer disease.

J Biol Chem2011PMID:21118811high

Abstract

Apolipoprotein (apo) E4 is the major genetic risk factor for late-onset Alzheimer disease (AD). ApoE4 assumes a pathological conformation through an intramolecular interaction mediated by Arg-61 in the amino-terminal domain and Glu-255 in the carboxyl-terminal domain, referred to as apoE4 domain interaction. Because AD is associated with mitochondrial dysfunction, we examined the effect of apoE4 domain interaction on mitochondrial respiratory function. Steady-state amounts of mitochondrial respiratory complexes were examined in neurons cultured from brain cortices of neuron-specific enolase promoter-driven apoE3 (NSE-apoE3) or apoE4 (NSE-apoE4) transgenic mice. All subunits of mitochondrial respiratory complexes assessed were significantly lower in NSE-apoE4 neurons compared with NSE-apoE3 neurons. However, no significant differences in levels of mitochondrial complexes were detected between astrocytes expressing different apoE isoforms driven by the glial fibrillary acidic protein promoter, leading to our conclusion that the effect of apoE4 is neuron specific. In neuroblastoma Neuro-2A (N2A) cells, apoE4 expression reduced the levels of mitochondrial respiratory complexes I, IV, and V. Complex IV enzymatic activity was also decreased, lowering mitochondrial respiratory capacity. Mutant apoE4 (apoE4-Thr-61) lacking domain interaction did not induce mitochondrial dysfunction in N2A cells, indicating that the effect is specific to apoE4-expressing cells and dependent on domain

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Novel natural structure corrector of ApoE4 for checking Alzheimer's disease: benefits from high throughput screening and molecular dynamics simulations.

Biomed Res Int2013PMID:24324968high

Abstract

A major genetic suspect for Alzheimer's disease is the pathological conformation assumed by apolipoprotein E4 (ApoE4) through intramolecular interaction. In the present study, a large library of natural compounds was screened against ApoE4 to identify novel therapeutic molecules that can prevent ApoE4 from being converted to its pathological conformation. We report two such natural compounds PHC and IAH that bound to the active site of ApoE4 during the docking process. The binding analysis suggested that they have a strong mechanistic ability to correct the pathological structural orientation of ApoE4 by preventing repulsion between Arg 61 and Arg 112, thus inhibiting the formation of a salt bridge between Arg 61 and Glu 255. However, when the molecular dynamics simulations were carried out, structural changes in the PHC-bound complex forced PHC to move out of the cavity thus destabilizing the complex. However, IAH was structurally stable inside the binding pocket throughout the simulations trajectory. Our simulations results indicate that the initial receptor-ligand interaction observed after docking could be limited due to the receptor rigid docking algorithm and that the conformations and interactions observed after simulation runs are more energetically favored and should be better representations of derivative poses in the receptor.

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Characterization of the N- and C-terminal domain interface of the three main apoE isoforms: A combined quantitative cross-linking mass spectrometry and molecular modeling study.

Biochim Biophys Acta Gen Subj2025PMID:39880049high

Abstract

Apolipoprotein E (apoE) polymorphism is associated with different pathologies such as atherosclerosis and Alzheimer's disease. Knowledge of the three-dimensional structure of apoE and isoform-specific structural differences are prerequisites for the rational design of small molecule structure modulators that correct the detrimental effects of pathological isoforms. In this study, cross-linking mass spectrometry (XL-MS) targeting Asp, Glu and Lys residues was used to explore the intramolecular interactions in the E2, E3 and E4 isoforms of apoE. The resulting quantitative XL-MS data combined with molecular modeling revealed isoform-specific characteristics of the N- and C-terminal domain interfaces as well as the isoform-dependent dynamic equilibrium of these interfaces. Finally, the data identified a network of salt bridges formed by R61-R112-E109 residues in the N-terminal helical bundle as a modulator of the interaction with the C-terminal domain making this network a potential drug target.

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Genome-wide association meta-analysis identifies 17 loci associated with nonalcoholic fatty liver disease.

Nat Genet2023PMID:37709864low

Abstract

Nonalcoholic fatty liver disease (NAFLD) is common and partially heritable and has no effective treatments. We carried out a genome-wide association study (GWAS) meta-analysis of imaging (n = 66,814) and diagnostic code (3,584 cases versus 621,081 controls) measured NAFLD across diverse ancestries. We identified NAFLD-associated variants at torsin family 1 member B (TOR1B), fat mass and obesity associated (FTO), cordon-bleu WH2 repeat protein like 1 (COBLL1)/growth factor receptor-bound protein 14 (GRB14), insulin receptor (INSR), sterol regulatory element-binding transcription factor 1 (SREBF1) and patatin-like phospholipase domain-containing protein 2 (PNPLA2), as well as validated NAFLD-associated variants at patatin-like phospholipase domain-containing protein 3 (PNPLA3), transmembrane 6 superfamily 2 (TM6SF2), apolipoprotein E (APOE), glucokinase regulator (GCKR), tribbles homolog 1 (TRIB1), glycerol-3-phosphate acyltransferase (GPAM), mitochondrial amidoxime-reducing component 1 (MARC1), microsomal triglyceride transfer protein large subunit (MTTP), alcohol dehydrogenase 1B (ADH1B), transmembrane channel like 4 (TMC4)/membrane-bound O-acyltransferase domain containing 7 (MBOAT7) and receptor-type tyrosine-protein phosphatase δ (PTPRD). Implicated genes highlight mitochondrial, cholesterol and de novo lipogenesis as causally contributing to NAFLD predisposition. Phenome-wide association study (PheWAS) analyses suggest at least seven subtypes of NAFLD. Individuals in the

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Activation of PPARA-mediated autophagy reduces Alzheimer disease-like pathology and cognitive decline in a murine model.

Autophagy2020PMID:30898012medium

Abstract

Alzheimer disease (AD) is the most common neurodegenerative disease. An imbalance between the production and clearance of Aβ (amyloid beta) is considered to be actively involved in AD pathogenesis. Macroautophagy/autophagy is a major cellular pathway leading to the removal of aggregated proteins, and upregulation of autophagy represents a plausible therapeutic strategy to combat overproduction of neurotoxic Aβ. PPARA/PPARα (peroxisome proliferator activated receptor alpha) is a transcription factor that regulates genes involved in fatty acid metabolism and activates hepatic autophagy. We hypothesized that PPARA regulates autophagy in the nervous system and PPARA-mediated autophagy affects AD. We found that pharmacological activation of PPARA by the PPARA agonists gemfibrozil and Wy14643 induces autophagy in human microglia (HM) cells and U251 human glioma cells stably expressing the human APP (amyloid beta precursor protein) mutant (APP-p.M671L) and this effect is PPARA-dependent. Administration of PPARA agonists decreases amyloid pathology and reverses memory deficits and anxiety symptoms in APP-PSEN1ΔE9 mice. There is a reduced level of soluble Aβ and insoluble Aβ in hippocampus and cortex tissues from APP-PSEN1ΔE9 mice after treatment with either gemfibrozil or Wy14643, which promoted the recruitment of microglia and astrocytes to the vicinity of Aβ plaques and enhanced autophagosome biogenesis. These results indicated that PPARA is an important factor regulating autophagy

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Discovery of a potent SCAP degrader that ameliorates HFD-induced obesity, hyperlipidemia and insulin resistance via an autophagy-independent lysosomal pathway.

Autophagy2021PMID:32432943low

Abstract

SCAP (SREBF chaperone) regulates SREBFs (sterol regulatory element binding transcription factors) processing and stability, and, thus, becomes an emerging drug target to treat dyslipidemia and fatty liver disease. However, the current known SCAP inhibitors, such as oxysterols, induce endoplasmic reticulum (ER) stress and NR1H3/LXRα (nuclear receptor subfamily 1 group H member 3)-SREBF1/SREBP-1 c-mediated hepatic steatosis, which severely limited the clinical application of this inhibitor. In this study, we identified a small molecule, lycorine, which binds to SCAP, which suppressed the SREBF pathway without inducing ER stress or activating NR1H3. Mechanistically, lycorine promotes SCAP lysosomal degradation in a macroautophagy/autophagy-independent pathway, a mechanism completely distinct from current SCAP inhibitors. Furthermore, we determined that SQSTM1 captured SCAP after its exit from the ER. The interaction of SCAP and SQSTM1 requires the WD40 domain of SCAP and the TB domain of SQSTM1. Interestingly, lycorine triggers the lysosome translocation of SCAP independent of autophagy. We termed this novel protein degradation pathway as the SQSTM1-mediated autophagy-independent lysosomal degradation (SMAILD) pathway. In vivo, lycorine ameliorates high-fat diet-induced hyperlipidemia, hepatic steatosis, and insulin resistance in mice. Our study demonstrated that the inhibition of SCAP through the SMAILD pathway could be employed as a useful therapeutic strategy for treating met

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Discovery and engineering of an anti-TREM2 antibody to promote amyloid plaque clearance by microglia in 5XFAD mice.

MAbs2022PMID:35921534medium

Abstract

Triggering receptor expressed on myeloid cells 2 (TREM2) plays a crucial role in regulating microglial functions and removal of amyloid plaques in Alzheimer's disease (AD). However, therapeutics based on this knowledge have not been developed due to the low antibody brain penetration and weak TREM2 activation. In this study, we engineered a TREM2 bispecific antibody to potently activate TREM2 and enter the brain. To boost TREM2 activation, we increased the valency of bivalent anti-TREM2 Ab2 IgG to tetra-variable domain immunoglobulin (TVD-Ig), thus improving the EC50 of amyloid-β oligomer (oAβ)-lipid microglial phagocytosis by more than 100-fold. Ab2 TVD-Ig treatment also augmented both microglia migration toward oAβ and microglia survival by 100-fold over the bivalent IgG antibody. By targeting the transferrin receptor (TfR), the brain-penetrating Ab2 TVD-Ig/αTfR bispecific antibody realized broad brain parenchyma distribution with a 10-fold increase in brain antibody concentration. Ab2 TVD-Ig/αTfR treatment of 5-month-old 5XFAD mice significantly boosted microglia-plaque interactions and enhanced amyloid plaque phagocytosis by microglia. Thus, potent TREM2 activation by a multivalent agonist antibody coupled with TfR-mediated brain entry can boost microglia clearance of amyloid plaques, which suggests the antibody has potential as an AD treatment.List of abbreviations AD: Alzheimer's disease; Ab: antibody; APOE: apolipoprotein E; Aβ: amyloid beta; BBB: blood-brain barrier;

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Efficient systemic CNS delivery of a therapeutic antisense oligonucleotide with a blood-brain barrier-penetrating ApoE-derived peptide.

Biomed Pharmacother2024PMID:38749176medium

Abstract

Antisense oligonucleotide (ASO) has emerged as a promising therapeutic approach for treating central nervous system (CNS) disorders by modulating gene expression with high selectivity and specificity. However, the poor permeability of ASO across the blood-brain barrier (BBB) diminishes its therapeutic success. Here, we designed and synthesized a series of BBB-penetrating peptides (BPP) derived from either the receptor-binding domain of apolipoprotein E (ApoE) or a transferrin receptor-binding peptide (THR). The BPPs were conjugated to phosphorodiamidate morpholino oligomers (PMO) that are chemically analogous to the 2'-O-(2-methoxyethyl) (MOE)-modified ASO approved by the FDA for treating spinal muscular atrophy (SMA). The BPP-PMO conjugates significantly increased the level of full-length SMN2 in the patient-derived SMA fibroblasts in a concentration-dependent manner with minimal to no toxicity. Furthermore, the systemic administration of the most potent BPP-PMO conjugates significantly increased the expression of full-length SMN2 in the brain and spinal cord of SMN2 transgenic adult mice. Notably, BPP8-PMO conjugate showed a 1.25-fold increase in the expression of full-length functional SMN2 in the brain. Fluorescence imaging studies confirmed that 78% of the fluorescently (Cy7)-labelled BPP8-PMO reached brain parenchyma, with 11% uptake in neuronal cells. Additionally, the BPP-PMO conjugates containing retro-inverso (RI) D-BPPs were found to possess extended half-lives com

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Multimodal biomarker AI techniques for early neurocognitive disorder diagnosis: A systematic review.

Artif Intell Med2026PMID:41921464medium

Abstract

BACKGROUND: Early diagnosis of Alzheimer's disease (AD) and related dementias remains challenging because no single biomarker sufficiently captures the complex and multifactorial nature of the underlying pathology. In recent years, multimodal artificial intelligence (AI) models capable of integrating heterogeneous data sources-such as neuroimaging, fluid biomarkers, genetics, and cognitive assessments-have emerged as a promising strategy to improve early detection and risk stratification. METHODS: We performed a PRISMA-guided systematic review (PROSPERO: CRD420251049848) of studies published from 2010 to 2025. We included 27 peer-reviewed studies applying AI/ML to ≥2 biomarker modalities for diagnostic classification or prognostic prediction (e.g., MCI-to-AD conversion), with an explicit emphasis on multimodal designs that incorporated at least one minimally invasive and/or widely deployable modality (e.g., cognitive tests, blood-based biomarkers, APOE/genetics, retinal imaging, or routine clinical features). Risk of bias was assessed using QUADAS-2. RESULTS: Across the 27 included studies, multimodal AI models generally outperformed the best unimodal baselines, particularly when combining complementary biological information (e.g., imaging with molecular or clinical features). Diagnostic tasks more often achieved high discrimination (frequently AUCs in the ~0.85-0.95 range under internal validation), whereas prognostic prediction-especially MCI-to-AD conversion-remained more

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ASS1 Promotes Atherosclerotic Inflammation Through the NLRP3/IL-33/ST2 Axis in Ox-LDL-Induced Foam Cells.

Front Biosci (Landmark Ed)2026PMID:41914296medium

Abstract

BACKGROUND: Atherosclerosis is a chronic inflammatory disease characterized by lipid-driven immune dysregulation. Argininosuccinate synthase 1 (ASS1) has been implicated in macrophage inflammation, yet its precise mechanistic role in foam cell-mediated vascular injury during atherosclerosis remains unclear. This study investigates whether ASS1 promotes disease progression via the NLRP3/IL-33/ST2 axis. METHODS: An in vitro foam cell model was established using phorbol 12-myristate 13-acetate (PMA)-differentiated U937 macrophages treated with oxidized low-density lipoprotein (ox-LDL). The role of ASS1 was assessed via knockdown (si-ASS1) and overexpression (ASS1 overexpression) plasmids. Co-culture systems with human umbilical vein endothelial cells (HUVECs) and human aortic vascular smooth muscle cells (HAVSMCs) were used to evaluate endothelial apoptosis and VSMC proliferation/migration. In vivo, atherosclerosis was induced in apolipoprotein E‑deficient (ApoE)-deficient mice via a 12-week high-fat diet, and ASS1 expression was modulated using AAV9 vectors. Molecular analyses included ROS detection, enzyme-linked immunosorbent assay (ELISA), qPCR, western blot, and immunofluorescence. Plaque burden was assessed via Oil Red O staining. RESULTS: Ox-LDL treatment significantly upregulated ASS1 expression in U937-derived foam cells. ASS1 overexpression enhanced intracellular ROS production, NLRP3 inflammasome activation, STAT3 phosphorylation, and IL-33 secretion. These effects we

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Cognitive Decline and Neurodegenerative Markers in Psoriasis: The Role of APOE4 and Beta-Amyloid.

Dermatol Pract Concept2026PMID:41912201medium

Abstract

INTRODUCTION: Psoriasis vulgaris (PV) is a chronic inflammatory skin disease increasingly recognized as a systemic disorder with potential cognitive implications. Amyloid beta (Aβ) and apolipoprotein E (APOE) are key proteins involved in Alzheimer's disease (AD) and neurodegeneration. OBJECTIVES: This study investigated the relationship between PV, cognitive function, and serum levels of Aβ and APOE4. METHODS: This case-control study was conducted on 80 participants: 50 PV patients and 30 age- and sex-matched controls. Clinical assessments included Psoriasis Area and Severity Index (PASI). Depression severity was assessed with Beck Depression Inventory-II (BDI-II), while cognitive function was evaluated using Montreal Cognitive Assessment (MoCA). Serum APOE4 and Aβ levels were measured using ELISA. RESULTS: Patients with PV exhibited significantly higher levels of APOE4 (1125.5 ± 232.1 ng/ml vs. 821.8 ± 266 ng/ml, P<0.001) and Aβ (21.4 ± 2.2 ng/ml vs. 18.7 ± 1.4 ng/ml, P<0.001) compared to controls. ROC analysis identified APOE4 (AUC=0.80, P<0.001) and Aβ (AUC=0.86, P<0.001) as significant predictors of PV. MoCA scores were significantly lower in PV patients (median=22 vs. 28, P<0.001), particularly in those with severe disease. APOE4 and Aβ levels negatively correlated with cognitive function (r= -0.418, P=0.003), and (r= -0.399, P=0.004) respectively. CONCLUSIONS: PV is associated with elevated Aβ and APOE4 levels, potentially linking chronic inflammation to neurodegenerati

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APOE4 domain interaction may have physiological roles; disrupting it could impair normal APOE4 functions in lipid metabolism

J Lipid Res2019PMID:30858636medium

Abstract

INTRODUCTION: Benzodiazepines are currently the gold standard for treatment of alcohol withdrawal. Gabapentin has growing evidence to support its use in the treatment of alcohol use disorder, however there is limited evidence regarding its role in the treatment of alcohol withdrawal. The purpose of this study was to determine if adjunctive gabapentin reduces the need for benzodiazepine (BZD) administration during alcohol withdrawal. METHODS: This was a retrospective single-center cohort study. Patients were included if they were 18-89 years old, had an underlying alcohol use disorder, and were initiated on the Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised (CIWA-Ar) protocol with or without scheduled gabapentin. They were excluded if they had a BZD use disorder, were on concomitant anti-epileptics, as-needed gabapentin, or BZDs outside the CIWA-Ar protocol. RESULTS: A total of 129 patients met inclusion criteria (n = 63 gabapentin group and 66 non-gabapentin group). There was a significant difference in as-needed BZD requirements, with the gabapentin group requiring a higher number of as-needed BZDs in the initial 72 hours of treatment (gabapentin 6 [IQR 0.5-10] non-gabapentin 2 [IQR 0-4]; p = 0.01) and overall (gabapentin 6 [IQR 0.5-10] vs. non-gabapentin 2 [IQR 0-5.5]; p = 0.01). The gabapentin group also had higher maximum CIWA-Ar scores in the initial 72 hours of treatment, and higher anxiety item scores in the initial 48 hours. CONCLUSION: Gabapentin

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Small molecule structure correctors (GIND-25, PH002) have not progressed to in vivo CNS studies, suggesting pharmacokinetic challenges

Nat Med2018PMID:29566794medium

Abstract

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Peptide therapeutics face manufacturing cost, stability, and immunogenicity challenges for chronic CNS administration

Nat Rev Drug Discov2020PMID:33122451medium

Abstract

Rho guanine nucleotide exchange factor 11 (ARHGEF11) has been proved to promote tumor metastasis in glioblastoma and ovarian carcinoma. However, the role of ARHGEF11 in hepatocellular carcinoma (HCC) progression is largely unknown. Here, we found that ARHGEF11 was upregulated in HCC samples and highly metastatic hepatoma cell lines. Knockdown of ARHGEFF11 inhibited the cell proliferation and invasion in both HCCLM3 and SKHEP1 cell lines. Subsequent mechanistic investigation showed that downregulation of ARHGEF11 significantly attenuated β-catenin nuclear translocation, thereafter repressed the expression of ZEB1 and cyclinD1, finally contributing to inhibition of epithelial-mesenchymal transition (EMT) and cell cycle arrest. Moreover, high levels of ARHGEF11 were found to be associated with shorter disease free and overall survival. A prognostic nomogram model that integrated ARHGEF11, tumor size and BCLC classification showed good performance in predicting clinical outcomes of HCC patients. Overall, this study demonstrated that ARHGEF11 could promote proliferation and metastasis of HCC via activating β-catenin pathway, suggesting that ARHGEF11 might serve as a potential prognostic biomarker for HCC.

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APOE4 risk may be primarily mediated through gain-of-toxic-function mechanisms that domain interaction correction alone cannot address

Nat Rev Neurosci2020PMID:33106633medium

Abstract

Genome-wide association studies of neurological diseases have identified thousands of variants associated with disease phenotypes. However, most of these variants do not alter coding sequences, making it difficult to assign their function. Here, we present a multi-omic epigenetic atlas of the adult human brain through profiling of single-cell chromatin accessibility landscapes and three-dimensional chromatin interactions of diverse adult brain regions across a cohort of cognitively healthy individuals. We developed a machine-learning classifier to integrate this multi-omic framework and predict dozens of functional SNPs for Alzheimer's and Parkinson's diseases, nominating target genes and cell types for previously orphaned loci from genome-wide association studies. Moreover, we dissected the complex inverted haplotype of the MAPT (encoding tau) Parkinson's disease risk locus, identifying putative ectopic regulatory interactions in neurons that may mediate this disease association. This work expands understanding of inherited variation and provides a roadmap for the epigenomic dissection of causal regulatory variation in disease.

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Intranasal Peptide Therapeutics: A Promising Avenue for Overcoming the Challenges of Traditional CNS Drug Development.

Cells2022PMID:36429060low

Abstract

The central nervous system (CNS) has, among all organ systems in the human body, the highest failure rate of traditional small-molecule drug development, ranging from 80-100% depending on the area of disease research. This has led to widespread abandonment by the pharmaceutical industry of research and development for CNS disorders, despite increased diagnoses of neurodegenerative disorders and the continued lack of adequate treatment options for brain injuries, stroke, neurodevelopmental disorders, and neuropsychiatric illness. However, new approaches, concurrent with the development of sophisticated bioinformatic and genomic tools, are being used to explore peptide-based therapeutics to manipulate endogenous pathways and targets, including "undruggable" intracellular protein-protein interactions (PPIs). The development of peptide-based therapeutics was previously rejected due to systemic off-target effects and poor bioavailability arising from traditional oral and systemic delivery methods. However, targeted nose-to-brain, or intranasal (IN), approaches have begun to emerge that allow CNS-specific delivery of therapeutics via the trigeminal and olfactory nerve pathways, laying the foundation for improved alternatives to systemic drug delivery. Here we review a dozen promising IN peptide therapeutics in preclinical and clinical development for neurodegenerative (Alzheimer's, Parkinson's), neuropsychiatric (depression, PTSD, schizophrenia), and neurodevelopmental disorders (a

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Agile delivery of protein therapeutics to CNS.

J Control Release2014PMID:24956489low

Abstract

A variety of therapeutic proteins have shown potential to treat central nervous system (CNS) disorders. Challenge to deliver these protein molecules to the brain is well known. Proteins administered through parenteral routes are often excluded from the brain because of their poor bioavailability and the existence of the blood-brain barrier (BBB). Barriers also exist to proteins administered through non-parenteral routes that bypass the BBB. Several strategies have shown promise in delivering proteins to the brain. This review, first, describes the physiology and pathology of the BBB that underscore the rationale and needs of each strategy to be applied. Second, major classes of protein therapeutics along with some key factors that affect their delivery outcomes are presented. Third, different routes of protein administration (parenteral, central intracerebroventricular and intraparenchymal, intranasal and intrathecal) are discussed along with key barriers to CNS delivery associated with each route. Finally, current delivery strategies involving chemical modification of proteins and use of particle-based carriers are overviewed using examples from literature and our own work. Whereas most of these studies are in the early stage, some provide proof of mechanism of increased protein delivery to the brain in relevant models of CNS diseases, while in few cases proof of concept had been attained in clinical studies. This review will be useful to broad audience of students, academic

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The Nasal-Brain Drug Delivery Route: Mechanisms and Applications to Central Nervous System Diseases.

MedComm (2020)2025PMID:40487748low

Abstract

The blood-brain barrier (BBB) is a highly selective and protective barrier that restricts the entry of most therapeutic agents into the central nervous system (CNS), posing a significant challenge for the treatment of CNS diseases. The nose-to-brain drug delivery (NBDD) route has emerged as a promising strategy to bypass the BBB, offering direct, noninvasive, and efficient transport of drugs to the brain. This review begins with a concise overview of the BBB structure and its biofunctions, followed by an in-depth discussion of the mechanisms underlying the nose-to-brain pathway, including the olfactory and trigeminal nerve routes, and respiratory pathway. We further highlight the therapeutic research development of neurodegenerative diseases, acute neurological diseases, brain tumor, and psychiatric disorders when using NBDD drugs encompassing small-molecule drugs, proteins, peptides, nucleic acids, siRNA, and herbal compounds, in which we also introduce innovative delivery systems, including nanocarriers and novel platforms such as exosomes, which enhance drug stability, targeting efficiency, and bioavailability. In addition, we provide a comprehensive overview of recent clinical advancements in therapeutics delivered via the intranasal route for CNS diseases. Finally, we discuss the challenges and future directions of NBDD, emphasizing its potential to transform the treatment landscape for CNS disorders.

Contradicts

Nanobiotechnology-based drug delivery in brain targeting.

Curr Pharm Biotechnol2013PMID:24910011low

Abstract

Blood brain barrier (BBB) found to act as rate limiting factor in drug delivery to brain in combating the central nervous system (CNS) disorders. Such limiting physiological factors include the reticuloendothelial system and protein opsonization, which present across BBB, play major role in reducing the passage of drug. Several approaches employed to improve the drug delivery across the BBB. Nanoparticles (NP) are the solid colloidal particle ranges from 1 to 1000 nm in size utilized as career for drug delivery. At present NPs are found to play a significant advantage over the other methods of available drug delivery systems to deliver the drug across the BBB. Nanoparticles may be because of its size and functionalization characteristics able to penetrate and facilitate the drug delivery through the barrier. There are number of mechanisms and strategies found to be involved in this process, which are based on the type of nanomaterials used and its combination with therapeutic agents, such materials include liposomes, polymeric nanoparticles and non-viral vectors of nano-sizes for CNS gene therapy, etc. Nanotechnology is expected to reduce the need for invasive procedures for delivery of therapeutics to the CNS. Some devices such as implanted catheters and reservoirs however will still be needed to overcome the problems in effective drug delivery to the CNS. Nanomaterials are found to improve the safety and efficacy level of drug delivery devices in brain targeting. Nanoeginee

Contradicts

Proteolysis-Targeting Chimera (PROTAC) Delivery into the Brain across the Blood-Brain Barrier.

Antibodies (Basel)2023PMID:37489365low

Abstract

Drug development for neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease has challenging difficulties due to the pharmacokinetic impermeability based on the blood-brain barrier (BBB) as well as the blurriness of pharmacodynamic targets based on their unclarified pathogenesis and complicated progression mechanisms. Thus, in order to produce innovative central nervous system (CNS) agents for patients suffering from CNS diseases, effective, selective delivery of CNS agents into the brain across the BBB should be developed. Currently, proteolysis-targeting chimeras (PROTACs) attract rising attention as a new modality to degrade arbitrary intracellular proteins by the ubiquitin-proteasome system. The internalizations of peptide-based PROTACs by cell-penetrating peptides and that of small molecule-based PROTACs through passive diffusion lack cell selectivity. Therefore, these approaches may bring off-target side effects due to wrong distribution. Furthermore, efflux transporters such as multiple drug resistance 1 (MDR1) expressed at the BBB might interrupt the entry of small molecule-based PROTACs into the brain. Nonetheless, intelligent delivery using machinery systems to absorb the nutrition into the brain for homeostasis, such as carrier-mediated transport (CMT) or receptor-mediated transcytosis (RMT), can be established. PROTACs with N-containing groups that are recognized by the proton-coupled organic cation antiporter might cr

Contradicts

Cyclic Opioid Peptides.

Curr Med Chem2016PMID:27117332medium

Abstract

For decades the opioid receptors have been an attractive therapeutic target for the treatment of pain. Since the first discovery of enkephalin, approximately a dozen endogenous opioid peptides have been known to produce opioid activity and analgesia, but their therapeutics have been limited mainly due to low blood brain barrier penetration and poor resistance to proteolytic degradation. One versatile approach to overcome these drawbacks is the cyclization of linear peptides to cyclic peptides with constrained topographical structure. Compared to their linear parents, cyclic analogs exhibit better metabolic stability, lower offtarget toxicity, and improved bioavailability. Extensive structure-activity relationship studies have uncovered promising compounds for the treatment of pain as well as further elucidate structural elements required for selective opioid receptor activity. The benefits that come with employing cyclization can be further enhanced through the generation of polycyclic derivatives. Opioid ligands generally have a short peptide chain and thus the realm of polycyclic peptides has yet to be explored. In this review, a brief history of designing ligands for the opioid receptors, including classic linear and cyclic ligands, is discussed along with recent approaches and successes of cyclic peptide ligands for the receptors. Various scaffolds and approaches to improve bioavailability are elaborated and concluded with a discourse towards polycyclic peptides.

Contradicts

Conformational Plasticity Enhances the Brain Penetration of a Metabolically Stable, Dual-Functional Opioid-Peptide CycloAnt.

Int J Mol Sci2024PMID:39518941medium

Abstract

CycloAnt is an opioid peptide that produces potent and efficacious antinociception with significantly reduced side effects upon systemic administration in mice. To verify its CNS-mediated antinociception, we determined its binding affinity at the opioid receptors, its proteolytic stability in mouse serum, metabolic stability in mouse liver microsomes, and pharmacokinetics in mice. CycloAnt exhibited stability toward proteolytic degradation in serum and resistance against metabolism mediated by cytochrome P450 enzymes (CYP450s) and UDP-glucuronosyl transferases (UGTs) in mouse liver microsomes. A pharmacokinetic study of CycloAnt in mice confirmed that CycloAnt crossed the blood-brain barrier (BBB) with a brain-to-plasma ratio of 11.5%, a high extent of BBB transport for a peptide. To elucidate the structural basis underlying its BBB penetration, we investigated its conformation in water and DMSO using 1H NMR spectroscopy. The results show that CycloAnt displays an extended conformation in water with most amide NHs being exposed, while in less polar DMSO, it adopts a compact conformation with all amide NHs locked in intramolecular hydrogen bonds. The chameleonic property helps CycloAnt permeate the BBB.

Contradicts

Systemic Administration of Neurotransmitter-Derived Lipidoids-PROTACs-DNA Nanocomplex Promotes Tau Clearance and Cognitive Recovery for Alzheimer's Disease Therapy.

Adv Healthc Mater2024PMID:39007278low

Abstract

Alzheimer's disease (AD) poses a significant burden on the economy and healthcare systems worldwide. Although the pathophysiology of AD remains debatable, its progression is strongly correlated with the accumulation of tau aggregates. Therefore, tau clearance from brain lesions can be a promising strategy for AD therapy. To achieve this, the present study combined proteolysis-targeting chimera (PROTAC), a novel protein-degradation technique that mediates degradation of target proteins via the ubiquitin-proteasome system, and a neurotransmitter-derived lipidoid (NT-lipidoid) nanoparticle delivery system with high blood-brain barrier-penetration activity, to generate a novel nanomedicine named NPD. Peptide 1, a cationic tau-targeting PROTAC is loaded onto the positively charged nanoparticles using DNA-intercalation technology. The resulting nanomedicine displayed good encapsulation efficiency, serum stability, drug release profile, and blood-brain barrier-penetration capability. Furthermore, NPD potently induced tau clearance in both cultured neuronal cells and the brains of AD mice. Moreover, intravenous injection of NPD led to a significant improvement in the cognitive function of the AD mice, without any remarkable abnormalities, thereby supporting its clinical development. Collectively, the novel nanomedicine developed in this study may serve as an innovative strategy for AD therapy, since it effectively and specifically induces tau protein clearance in brain lesions, which

Contradicts

Alzheimer's Disease: From Pathogenesis to Emerging Therapeutic Targets.

J Clin Med2026PMID:41899281medium

Abstract

Alzheimer's disease (AD) is the most prevalent cause of dementia and can be conceptualized as a tauopathy initiated by the accumulation of amyloid-β (Aβ) in the brain. The clinical introduction of anti-Aβ antibody therapies has marked the beginning of a new era in disease-modifying treatment for dementia. While the deleterious effects of Aβ on postsynaptic spines and axonal microtubules have been increasingly clarified, recent studies have shifted attention beyond extracellular Aβ deposition as senile plaques to the pathogenic significance of intracellular Aβ. In particular, accumulating evidence highlights lysosomes as critical sites of intracellular Aβ toxicity. Interactions between Aβ and gangliosides, v-ATPase-dependent lysosomal acidification, and lysosomal membrane integrity are the key determinants of disease progression. In parallel, additional molecular players, including components of the complement cascade and asparaginyl endopeptidase, have been implicated in linking Aβ pathology to tau dysregulation and neurodegeneration. As therapeutic strategies targeting Aβ enter clinical practice, these emerging pathways represent promising targets for the next generation of AD treatment. Here, we summarize current insights and ongoing therapeutic developments centered on these mechanisms.

Contradicts

Association of Periodontal Pathogens and Their Inflammatory Mediators With Alzheimer's Disease Neurodegeneration: A Systematic Review.

Cureus2026PMID:41890452medium

Abstract

Periodontitis is implicated in a range of systemic conditions, including cardiovascular disease, diabetes, and respiratory disorders. Emerging evidence suggests a link between periodontal infection, inflammation, and the neurodegenerative process of Alzheimer's disease (AD). This paper aimed to systematically review observational studies examining the association of periodontal pathogens and their inflammatory products with AD neurodegeneration. The review was registered in the International Prospective Register of Systematic Reviews (PROSPERO - No. CRD42020150043). Methods followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. An electronic search (PubMed/Medical Literature Analysis and Retrieval System Online (MEDLINE), Web of Science, Scopus, Cochrane Library, grey literature) was conducted until September 2025 with no language or date restrictions. Two independent reviewers screened and extracted data. The risk of bias was assessed via the Risk Of Bias In Non-randomized Studies - of Exposures (ROBINS‑E) tool. Of 1,421 identified citations, eight studies met the inclusion criteria. Participant numbers ranged from 349 to 2,191, and ages ranged from 40 to 90 years old. Meta‑analysis was not feasible due to methodological heterogeneity. Risk of bias was moderate in five studies and serious in three. Findings indicated that higher serum IgG antibodies to periodontal pathogens and elevated inflammatory mediators, notably tumor necro

Contradicts

Can we refute a role for infections in Alzheimer's disease pathogenesis?

Alzheimers Dement2026PMID:41867029medium

Abstract

While a growing body of literature suggests a role for infections in Alzheimer's disease (AD), microbial contributions to AD remains a contentious topic, in part due to challenges in reconciling the positive evidence with studies reporting null findings. Here, we examine the evidence that argues against a role for infections in AD, while offering mechanistic hypotheses that may account for both the negative and positive findings, including dysregulated host immunity and gene-environment interactions of AD-associated genes.

📖 Linked Papers (30)Export BibTeX ↗

J Alzheimers Dis (2026) · PubMed:41930593 ↗

1 figure

Figures

Figures available at source paper (no open-access XML found).

Cognitive Decline and Neurodegenerative Markers in Psoriasis: The Role of APOE4 and Beta-Amyloid.

Dermatology practical & conceptual (2026) · PubMed:41912201 ↗

3 figures

Figure 1

A) APOE4 and B) beta-amyloid serum levels (ng/ml) in the studied groups.

Figure 2

ROC analysis of A) APOE4 and B) Beta-amyloid to diagnose PV.

Plasma GFAP outperforms CSF GFAP in detecting amyloid pathology and is associated with increased risk of clinical progression in early Alzheimer's disease.

The journal of prevention of Alzheimer's disease (2026) · PubMed:41905188 ↗

4 figures

Fig. 1

Biomarker Levels in Plasma and CSF across Different Groups. (A) Plasma GFAP (Glial Fibrillary Acidic Protein) levels (pg/ml) across subject groups, including h...

Fig. 2

Biomarker Levels in Plasma and CSF Based on Amyloid-β Status. (A) Plasma GFAP levels (pg/ml) in the same groups. Plasma GFAP concentrations in SCD-A+, MCI-A+, ...

Alzheimer's Disease: From Pathogenesis to Emerging Therapeutic Targets.

Journal of clinical medicine (2026) · PubMed:41899281 ↗

1 figure

Figures

Figures available at source paper (no open-access XML found).

Association of Periodontal Pathogens and Their Inflammatory Mediators With Alzheimer's Disease Neurodegeneration: A Systematic Review.

Cureus (2026) · PubMed:41890452 ↗

1 figure

Figure 1

PRISMA flowchart. PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses; MEDLINE: Medical Literature Analysis and Retrieval System Online

Can we refute a role for infections in Alzheimer's disease pathogenesis?

Alzheimer's & dementia : the journal of the Alzheimer's Association (2026) · PubMed:41867029 ↗

1 figure

Figures

Figures available at source paper (no open-access XML found).

Modulation of apolipoprotein E receptor-2 by ApoE4, amyloid β-peptide, reelin, and secreted amyloid precursor protein: a common point of impact in Alzheimer's disease pathogenesis.

Frontiers in molecular neuroscience (2026) · PubMed:41858499 ↗

1 figure

Figures

Figures available at source paper (no open-access XML found).

Menopause, cognition, and Alzheimer's disease risk.

Curr Opin Obstet Gynecol (2026) · PubMed:41531227 ↗

1 figure

Figures

Figures available at source paper (no open-access XML found).

Integrative machine learning approach to risk prediction for dementia and Alzheimer's disease.

Geroscience (2026) · PubMed:40864401 ↗

5 figures

Fig. 1

Age matching protocol. A The distribution of the control and AD groups by age. B Following a protocol for age-matching schemes, a major cofounding bias was ...

Fig. 2

Performance of the risk factor predictive modes for AD from UKB. A Comparison of selected models’ performance by the mean of the ROC-AUC for ten different ind...

Increased genetic protection against Alzheimer's disease in centenarians.

Geroscience (2026) · PubMed:40615639 ↗

1 figure

Figures

Figures available at source paper (no open-access XML found).

Perioperative polygenic and APOE-based genetic risk assessment for neurocognitive disorders: a biobank study.

Br J Anaesth (2026) · PubMed:40562635 ↗

1 figure

Figures

Figures available at source paper (no open-access XML found).

Neuropsychiatric symptoms and apolipoprotein E genotypes in neurocognitive disorders.

Neural regeneration research (2026) · PubMed:40145985 ↗

3 figures

Figure 1

The mediating role of the apolipoprotein E gene in neurodegenerative and vascular disorders. The image illustrates the key role of the apolipoprotein E gene ( A...

Figure 2

Neuropsychiatric symptoms in AD and the role of the apolipoprotein E gene. AD can lead to neuropsychiatric symptoms such as apathy, agitation, aggression, depre...

📙 Related Wiki Pages (15)

APOE — Apolipoprotein Egene Composite Claim: Protein Aggregation Becconvergence_synthesis TGF-β Activator Therapy for Neurodegeneridea Globus Pallidus Externus GABAergic in Necell Axon Guidance Pathways in Neurodegeneratmechanism Computational Drug Discovery in Neurodegmechanism Sigma-1 Receptor Agonists for Neurodegentherapeutic Epigenetic Dysregulation in Neurodegenermechanism Tunneling Nanotubes in Neurodegenerationmechanism Ribonuclease κ and Circular RNAs: A New mechanism GSK3 Beta in Neurodegenerationmechanism Hippocampal Granule Cells in Neurodegenecell BDNF Signaling Pathway in Neurodegeneratmechanism Parabrachial Nucleus in Neurodegeneratiocell Microglial Priming and Innate Immune Toltherapeutic

Prediction	Predicted	Observed	Status	Conf
NMR/X-ray crystallography of proposed hinge region with and without small molecule modulators	Confirmatory evidence for hypothesis	— no observation —	pending	0.30
Comparative binding studies showing selectivity for APOE4 vs APOE3	Confirmatory evidence for hypothesis	— no observation —	pending	0.30
Pharmacokinetic studies in non-human primates measuring CNS penetration	Confirmatory evidence for hypothesis	— no observation —	pending	0.30
Single-cell RNA-seq to measure editing efficiency across different CNS cell types	Confirmatory evidence for hypothesis	— no observation —	pending	0.30
Genome-wide off-target analysis in edited brain tissue	Confirmatory evidence for hypothesis	— no observation —	pending	0.30
Longitudinal cognitive testing in edited vs. control animals	Confirmatory evidence for hypothesis	— no observation —	pending	0.30
Biochemical binding assays measuring PROTAC selectivity for APOE4 vs APOE3	Confirmatory evidence for hypothesis	— no observation —	pending	0.30
Mass spectrometry-based degradation kinetics in primary neurons	Confirmatory evidence for hypothesis	— no observation —	pending	0.30
BBB penetration studies with radiolabeled PROTACs	Confirmatory evidence for hypothesis	— no observation —	pending	0.30
Surface plasmon resonance measuring competitive binding vs. natural phospholipids	Confirmatory evidence for hypothesis	— no observation —	pending	0.30
Thermal shift assays demonstrating domain separation in presence of mimetics	Confirmatory evidence for hypothesis	— no observation —	pending	0.30
Lipidomics analysis showing mimetics don't disrupt normal lipid metabolism	Confirmatory evidence for hypothesis	— no observation —	pending	0.30
Mass spectrometry mapping of APOE4 glycosylation sites	Confirmatory evidence for hypothesis	— no observation —	pending	0.30
Enzymatic deglycosylation studies measuring effects on domain interaction	Confirmatory evidence for hypothesis	— no observation —	pending	0.30
Proteomics analysis of off-target glycosylation changes	Confirmatory evidence for hypothesis	— no observation —	pending	0.30
Fluorescence polarization assays measuring peptide binding specificity	Confirmatory evidence for hypothesis	— no observation —	pending	0.30
Stability studies in cerebrospinal fluid and brain homogenates	Confirmatory evidence for hypothesis	— no observation —	pending	0.30
Biodistribution studies tracking peptide localization in brain	Confirmatory evidence for hypothesis	— no observation —	pending	0.30
Single-molecule FRET studies measuring APOE4 conformational dynamics with/without chaperone overexpression	Confirmatory evidence for hypothesis	— no observation —	pending	0.30
Proteostasis network analysis showing chaperone client specificity	Confirmatory evidence for hypothesis	— no observation —	pending	0.30
Long-term toxicity studies of sustained chaperone upregulation	Confirmatory evidence for hypothesis	— no observation —	pending	0.30

Competitive APOE4 Domain Stabilization Peptides

Competitive APOE4 Domain Stabilization Peptides

🧪 Overview

Mechanistic Overview

Mechanistic Overview

Mechanistic Pathway Diagram

Molecular and Cellular Rationale

APOE

Evidence Supporting the Hypothesis

Contradictory Evidence, Caveats, and Failure Modes

Clinical and Translational Relevance

Experimental Predictions and Validation Strategy

Decision-Oriented Summary

🧬 Mechanism

⚖️ Evidence

🏥 Translation

🧬 3D Protein Structure — APOE

💉 Clinical Trials (14)Relevance: 72%

🏆 Tournament

🏆 Arenas / Elo

📊 Market Indicators

💾 Resource Usage

🔮 Predictions

📖 References (10)

Competitive APOE4 Domain Stabilization Peptides

Competitive APOE4 Domain Stabilization Peptides

🧪 Overview

Mechanistic Overview

Mechanistic Overview

Mechanistic Pathway Diagram

Molecular and Cellular Rationale

APOE

Evidence Supporting the Hypothesis

Contradictory Evidence, Caveats, and Failure Modes

Clinical and Translational Relevance

Experimental Predictions and Validation Strategy

Decision-Oriented Summary

🧬 Mechanism

⚖️ Evidence

🏥 Translation

🧬 3D Protein Structure — APOE

💉 Clinical Trials (14)Relevance: 72%

🏆 Tournament

🏆 Arenas / Elo

📊 Market Indicators

💾 Resource Usage

🧭 Related

associated with (8)

causes (3)

co chaperone (1)

co discussed (13)

determines (1)

enhances (1)

impairs (1)

implicated in (1)

inhibits (1)

interacts with (14)

maintains (1)

participates in (3)

regulates (2)

🔮 Predictions

📖 References (10)