Engineered Apolipoprotein E4-Neutralizing Shuttle Peptides
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From Analysis:
Blood-brain barrier transport mechanisms for antibody therapeutics
Anti-amyloid antibodies (lecanemab, donanemab) have ~0.1% brain penetrance. Engineering improved BBB transcytosis via transferrin receptor, LRP1, or novel shuttle peptides could dramatically improve efficacy.
Hypotheses from Same Analysis (6)
These hypotheses emerged from the same multi-agent debate that produced this hypothesis.
Description
Molecular Mechanism and Rationale
The apolipoprotein E4 (ApoE4) isoform represents the most significant genetic risk factor for late-onset Alzheimer's disease, present in approximately 40-65% of patients compared to 15% of the general population. Unlike the protective ApoE2 and neutral ApoE3 isoforms, ApoE4 exhibits distinct structural conformational changes that drive pathological cascades in neurodegeneration. The proposed engineered ApoE4-neutralizing shuttle peptides exploit the endogenous ApoE receptor system while simultaneously counteracting ApoE4's toxic effects through a sophisticated bifunctional design.
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✓ Supporting Evidence 17
The low-density lipoprotein receptor (LDLR) gene family includes LDLR, very LDLR, and LDL receptor-related proteins (LRPs) such as LRP1, LRP1b (aka LRP-DIT), LRP2 (aka megalin), LRP4, and LRP5/6, and LRP8 (aka ApoER2). LDLR family members constitute a class of closely related multifunctional, transmembrane receptors, with diverse functions, from embryonic development to cancer, lipid metabolism, and cardiovascular homeostasis. While LDLR family members have been studied extensively in the systemic circulation in the context of atherosclerosis, their roles in pulmonary arterial hypertension (PAH) are understudied and largely unknown. Endothelial dysfunction, tissue infiltration of monocytes, and proliferation of pulmonary artery smooth muscle cells are hallmarks of PAH, leading to vascular remodeling, obliteration, increased pulmonary vascular resistance, heart failure, and death. LDLR family members are entangled with the aforementioned detrimental processes by controlling many pathways that are dysregulated in PAH; these include lipid metabolism and oxidation, but also platelet-derived growth factor, transforming growth factor β1, Wnt, apolipoprotein E, bone morpohogenetic proteins, and peroxisome proliferator-activated receptor gamma. In this paper, we discuss the current knowledge on LDLR family members in PAH. We also review mechanisms and drugs discovered in biological contexts and diseases other than PAH that are likely very relevant in the hypertensive pulmonary vascul
Among the LDL receptor (LDLR) family members, the roles of LDLR-related protein (LRP)1 in the pathogenesis of Alzheimer's disease (AD), especially late-onset AD, have been the most studied by genetic, neuropathological, and biomarker analyses (clinical studies) or cellular and animal model systems (preclinical studies) over the last 25 years. Although there are some conflicting reports, accumulating evidence from preclinical studies indicates that LRP1 not only regulates the metabolism of amyloid-β peptides (Aβs) in the brain and periphery, but also maintains brain homeostasis, impairment of which likely contributes to AD development in Aβ-independent manners. Several preclinical studies have also demonstrated an involvement of LRP1 in regulating the pathogenic role of apoE, whose gene is the strongest genetic risk factor for AD. Nonetheless, evidence from clinical studies is not sufficient to conclude how LRP1 contributes to AD development. Thus, despite very promising results from preclinical studies, the role of LRP1 in AD pathogenesis remains to be further clarified. In this review, we discuss the potential mechanisms underlying how LRP1 affects AD pathogenesis through Aβ-dependent and -independent pathways by reviewing both clinical and preclinical studies. We also discuss potential therapeutic strategies for AD by targeting LRP1.
RATIONALE: Atherosclerosis is, in part, caused by immune and inflammatory cell infiltration into the vascular wall, leading to enhanced inflammation and lipid accumulation in the aortic endothelium. Understanding the molecular mechanisms underlying this disease is critical for the development of new therapies. Our recent studies demonstrate that epsins, a family of ubiquitin-binding endocytic adaptors, are critical regulators of atherogenicity. Given the fundamental contribution lesion macrophages make to fuel atherosclerosis, whether and how myeloid-specific epsins promote atherogenesis is an open and significant question. OBJECTIVE: We will determine the role of myeloid-specific epsins in regulating lesion macrophage function during atherosclerosis. METHODS AND RESULTS: We engineered myeloid cell-specific epsins double knockout mice (LysM-DKO) on an ApoE-/- background. On Western diet, these mice exhibited marked decrease in atherosclerotic lesion formation, diminished immune and inflammatory cell content in aortas, and reduced necrotic core content but increased smooth muscle cell content in aortic root sections. Epsins deficiency hindered foam cell formation and suppressed proinflammatory macrophage phenotype but increased efferocytosis and anti-inflammatory macrophage phenotype in primary macrophages. Mechanistically, we show that epsin loss specifically increased total and surface levels of LRP-1 (LDLR [low-density lipoprotein receptor]-related protein 1), an efferocyto
ApoE-Corona oncolytic adenovirus nanoparticles enable blood-brain barrier penetration for glioblastoma immunot… MEDIUM▼
Oncolytic adenovirus (OA) therapy, an emerging cancer immunotherapy, is on the rise. However, intravenous delivery of OA has not yielded success in the treatment of glioblastoma (GBM) due to inefficient blood-brain barrier (BBB) penetration and poor glioma-targeting effectiveness. Therefore, oncolytic adenovirus nanoparticles (OA@Aβ-am NPs) have been successfully designed for efficient targeted delivery to GBM. The prepared platform uses OA as the core and then interacts with apolipoprotein E (ApoE) and LDLR-associated protein 1 (LRP1), which is overexpressed within glioma, as the target. Modified amyloid beta peptide (Aβ-am) actively accumulates ApoE in plasma to form a protein corona and promotes binding to LRP1, thus achieving dual targeting of the BBB and GBM. In addition, systematic studies confirm that OA@Aβ-am NPs possess excellent targeting ability and can prolong the survival of in situ GBM-bearing mice. OA@Aβ-am NPs can induce anti-tumor immune responses after reaching the GBM site, turning the "cold" GBM into a "hot" tumor and causing immunogenic cell death (ICD). In summary, this constructed OA@Aβ-am NP platform provides a promising strategy for oncolytic adenovirus-targeted therapy for GBM.
Apolipoprotein E (APOE) genotype is the major genetic risk factor for Alzheimer disease (AD); the ε4 allele increases risk and the ε2 allele is protective. In the central nervous system (CNS), apoE is produced by glial cells, is present in high-density-like lipoproteins, interacts with several receptors that are members of the low-density lipoprotein receptor (LDLR) family, and is a protein that binds to the amyloid-β (Aβ) peptide. There are a variety of mechanisms by which apoE isoform may influence risk for AD. There is substantial evidence that differential effects of apoE isoform on AD risk are influenced by the ability of apoE to affect Aβ aggregation and clearance in the brain. Other mechanisms are also likely to play a role in the ability of apoE to influence CNS function as well as AD, including effects on synaptic plasticity, cell signaling, lipid transport and metabolism, and neuroinflammation. ApoE receptors, including LDLRs, Apoer2, very low-density lipoprotein receptors (VLDLRs), and lipoprotein receptor-related protein 1 (LRP1) appear to influence both the CNS effects of apoE as well as Aβ metabolism and toxicity. Therapeutic strategies based on apoE and apoE receptors may include influencing apoE/Aβ interactions, apoE structure, apoE lipidation, LDLR receptor family member function, and signaling. Understanding the normal and disease-related biology connecting apoE, apoE receptors, and AD is likely to provide novel insights into AD pathogenesis and treatment.
Human studies support a strong association between hypertriglyceridemia and atherosclerotic cardiovascular disease (CVD). However, whether a causal relationship exists between hypertriglyceridemia and increased CVD risk is still unclear. One plausible explanation for the difficulty establishing a clear causal role for hypertriglyceridemia in CVD risk is that lipolysis products of triglyceride-rich lipoproteins (TRLs), rather than the TRLs themselves, are the likely mediators of increased CVD risk. This hypothesis is supported by studies of rare mutations in humans resulting in impaired clearance of such lipolysis products (remnant lipoprotein particles; RLPs). Several animal models of hypertriglyceridemia support this hypothesis and have provided additional mechanistic understanding. Mice deficient in lipoprotein lipase (LPL), the major vascular enzyme responsible for TRL lipolysis and generation of RLPs, or its endothelial anchor GPIHBP1, are severely hypertriglyceridemic but develop only minimal atherosclerosis as compared with animal models deficient in apolipoprotein (APO) E, which is required to clear TRLs and RLPs. Likewise, animal models convincingly show that increased clearance of TRLs and RLPs by LPL activation (achieved by inhibition of APOC3, ANGPTL3, or ANGPTL4 action, or increased APOA5) results in protection from atherosclerosis. Mechanistic studies suggest that RLPs are more atherogenic than large TRLs because they more readily enter the artery wall, and becau
Alzheimer's disease (AD) is a chronic neurodegenerative disease associated with intracerebral accumulation of aggregated amyloid-beta (Aβ) and tau proteins, as well as neuroinflammation. Human intravenous immunoglobulin (IVIG) is a mixture of polyclonal IgG antibodies isolated and pooled from thousands of healthy human donors. The scientific rationale for testing IVIG as a potential AD treatment include its natural anti-Aβ antibody activity, its favorable safety profile and inherent anti-inflammatory/immunomodulatory properties. Over the past decade, several clinical and pre-clinical experimental findings, advanced our knowledge about biological and therapeutic properties of IVIG that are relevant to AD therapy. Anti-amyloid antibodies in IVIG show significantly higher binding avidity for amyloid oligomers and fibrils than for Aβ monomers. In a double transgenic murine model of AD, intracerebral injection of IVIG causes suppression of Aβ fibril pathology whereas long term peripheral IVIG treatments causes elevation of total brain Aβ levels with no measurable impact on Aβ deposits or tendency for inducing cerebral microhemmorhage. Furthermore, chronic IVIG treatment suppressed neuroinflammation and fostered adult hippocampal neurogenesis. In clinical studies with AD patients, IVIG showed an acceptable safety profile and has not been reported to increase the incidence of amyloid related imaging abnormalities. Preliminary studies on small number of patients reported clinical ben
Monoclonal antibodies against β-amyloid (Aβ) for the treatment of Alzheimer's disease: the Aβ target at a cros… STRONG▼
Several second-generation active β-amyloid (Aβ) vaccines and passive Aβ immunotherapies are under clinical investigation with the aim of boosting Aβ clearance from the brain of the Alzheimer's disease (AD) patients. However, the preliminary cognitive efficacy of bapineuzumab, a humanized anti-Aβ monoclonal antibody, appears uncertain. Moreover, the occurrence of vasogenic edema and, more rarely, brain microhemorrhages, especially in apolipoprotein E ϵ4 carriers, have led to abandoning of the highest dose of the drug. Solanezumab, another humanized anti-Aβ monoclonal antibody, was shown to neutralize soluble Aβ oligomers, which is believed to be the more neurotoxic Aβ species. Phase II studies showed a good safety profile of solanezumab while studies on cerebrospinal and plasma biomarkers documented good signals of pharmacodynamic activity. However, the preliminary equivocal cognitive results obtained with bapineuzumab as well as the detrimental cognitive effects observed with semagacestat, a potent γ-secretase inhibitor, raise the possibility that targeting Aβ may not be clinically efficacious in AD. The results of four ongoing large Phase III trials on bapineuzumab and two Phase III trials on solanezumab will tell us if passive anti-Aβ immunization is able to alter the course of this devastating disease, and if Aβ is still a viable target for anti-AD drugs.
The majority of therapies that target individual proteins rely on specific activity-modulating interactions with the target protein-for example, enzyme inhibition or ligand blocking. However, several major classes of therapeutically relevant proteins have unknown or inaccessible activity profiles and so cannot be targeted by such strategies. Protein-degradation platforms such as proteolysis-targeting chimaeras (PROTACs)1,2 and others (for example, dTAGs3, Trim-Away4, chaperone-mediated autophagy targeting5 and SNIPERs6) have been developed for proteins that are typically difficult to target; however, these methods involve the manipulation of intracellular protein degradation machinery and are therefore fundamentally limited to proteins that contain cytosolic domains to which ligands can bind and recruit the requisite cellular components. Extracellular and membrane-associated proteins-the products of 40% of all protein-encoding genes7-are key agents in cancer, ageing-related diseases and autoimmune disorders8, and so a general strategy to selectively degrade these proteins has the potential to improve human health. Here we establish the targeted degradation of extracellular and membrane-associated proteins using conjugates that bind both a cell-surface lysosome-shuttling receptor and the extracellular domain of a target protein. These initial lysosome-targeting chimaeras, which we term LYTACs, consist of a small molecule or antibody fused to chemically synthesized glycopeptide
Alzheimer's disease (AD) is the most common cause of dementia worldwide, and its prevalence is rapidly increasing due to extended lifespans. Among the increasing number of genetic risk factors identified, the apolipoprotein E (APOE) gene remains the strongest and most prevalent, impacting more than half of all AD cases. While the ε4 allele of the APOE gene significantly increases AD risk, the ε2 allele is protective relative to the common ε3 allele. These gene alleles encode three apoE protein isoforms that differ at two amino acid positions. The primary physiological function of apoE is to mediate lipid transport in the brain and periphery; however, additional functions of apoE in diverse biological functions have been recognized. Pathogenically, apoE seeds amyloid-β (Aβ) plaques in the brain with apoE4 driving earlier and more abundant amyloids. ApoE isoforms also have differential effects on multiple Aβ-related or Aβ-independent pathways. The complexity of apoE biology and pathobiology presents challenges to designing effective apoE-targeted therapeutic strategies. This review examines the key pathobiological pathways of apoE and related targeting strategies with a specific focus on the latest technological advances and tools.
The impact of apolipoprotein E ε4 (APOE4), the strongest genetic risk factor for Alzheimer's disease (AD), on human brain cellular function remains unclear. Here, we investigated the effects of APOE4 on brain cell types derived from population and isogenic human induced pluripotent stem cells, post-mortem brain, and APOE targeted replacement mice. Population and isogenic models demonstrate that APOE4 local haplotype, rather than a single risk allele, contributes to risk. Global transcriptomic analyses reveal human-specific, APOE4-driven lipid metabolic dysregulation in astrocytes and microglia. APOE4 enhances de novo cholesterol synthesis despite elevated intracellular cholesterol due to lysosomal cholesterol sequestration in astrocytes. Further, matrisome dysregulation is associated with upregulated chemotaxis, glial activation, and lipid biosynthesis in astrocytes co-cultured with neurons, which recapitulates altered astrocyte matrisome signaling in human brain. Thus, APOE4 initiates glia-specific cell and non-cell autonomous dysregulation that may contribute to increased AD risk.
APOE ε4 allele (ApoE4) is the primary genetic risk factor for sporadic Alzheimer's disease (AD), expressed in 40-65% of all AD patients. ApoE4 has been associated to many pathological processes possibly linked to cognitive impairment, such as amyloid-β (Aβ) and tau pathologies. However, the exact mechanism underlying ApoE4 impact on AD progression is unclear, while no effective therapies are available for this highly debilitating neurodegenerative disorder. This review describes the current knowledge of ApoE4 interaction with mitochondria, causing mitochondrial dysfunction and neurotoxicity, associated with increased mitochondrial Ca2+ and reactive oxygen species (ROS) levels, and it effects on mitochondrial dynamics, namely fusion and fission, and mitophagy. Moreover, ApoE4 translocates to the nucleus, regulating the expression of genes involved in aging, Aβ production, inflammation and apoptosis, potentially linked to AD pathogenesis. Thus, novel therapeutical targets can be envisaged to counteract the effects induced by ApoE4 in AD brain.
Historically considered as accessory cells to neurons, there is an increasing interest in the role of astrocytes in normal and pathological conditions. Astrocytes are involved in neurotransmitter recycling, antioxidant supply, ion buffering and neuroinflammation, i.e. a lot of the same pathways that go astray in Alzheimer's disease (AD). AD remains the leading cause of dementia in the elderly, one for which there is still no cure. Efforts in AD drug development have largely focused on treating neuronal pathologies that appear relatively late in the disease. The neuroenergetic hypothesis, however, focuses on the early event of glucose hypometabolism in AD, where astrocytes play a key role, caused by an imbalanced neuron-astrocyte lactate shuttle. This further results in a state of oxidative stress and neuroinflammation, thereby compromising the integrity of astrocyte-neuron interaction. Compromised astrocytic energetics also enhance amyloid generation, further increasing the severity of the disease. Additionally, apolipoprotein E (APOE), the major genetic risk factor for AD, is predominantly secreted by astrocytes and plays a critical role in amyloid clearance and regulates glucose metabolism in an amyloid-independent manner. Thus, boosting the neuroprotective properties of astrocytes has potential applications in delaying the onset and progression of AD. This review explores how the metabolic dysfunction arising from astrocytes acts as a trigger for the development of AD.
Mitochondrial intracrines are extracellular signaling proteins, targeted to the mitochondria. The pathway for mitochondrial targeting of mitochondrial intracrines and actions in the mitochondria remains unknown. Megalin/LRP2 mediates the uptake of vitamins and proteins, and is critical for clearance of amyloid-β protein from the brain. Megalin mutations underlie the pathogenesis of Donnai-Barrow and Lowe syndromes, characterized by brain defects and kidney dysfunction; megalin was not previously known to reside in the mitochondria. Here, we show megalin is present in the mitochondria and associates with mitochondrial anti-oxidant proteins SIRT3 and stanniocalcin-1 (STC1). Megalin shuttles extracellularly-applied STC1, angiotensin II and TGF-β to the mitochondria through the retrograde early endosome-to-Golgi transport pathway and Rab32. Megalin knockout in cultured cells impairs glycolytic and respiratory capacities. Thus, megalin is critical for mitochondrial biology; mitochondrial intracrine signaling is a continuum of the retrograde early endosome-to-Golgi-Rab32 pathway and defects in this pathway may underlie disease processes in many systems.
Apolipoprotein E (Apo-E) is a major cholesterol carrier that supports lipid transport and injury repair in the brain. APOE polymorphic alleles are the main genetic determinants of Alzheimer disease (AD) risk: individuals carrying the ε4 allele are at increased risk of AD compared with those carrying the more common ε3 allele, whereas the ε2 allele decreases risk. Presence of the APOE ε4 allele is also associated with increased risk of cerebral amyloid angiopathy and age-related cognitive decline during normal ageing. Apo-E-lipoproteins bind to several cell-surface receptors to deliver lipids, and also to hydrophobic amyloid-β (Aβ) peptide, which is thought to initiate toxic events that lead to synaptic dysfunction and neurodegeneration in AD. Apo-E isoforms differentially regulate Aβ aggregation and clearance in the brain, and have distinct functions in regulating brain lipid transport, glucose metabolism, neuronal signalling, neuroinflammation, and mitochondrial function. In this Review, we describe current knowledge on Apo-E in the CNS, with a particular emphasis on the clinical and pathological features associated with carriers of different Apo-E isoforms. We also discuss Aβ-dependent and Aβ-independent mechanisms that link Apo-E4 status with AD risk, and consider how to design effective strategies for AD therapy by targeting Apo-E.
BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder distinguished by a swift cognitive deterioration accompanied by distinctive pathological hallmarks such as extracellular Aβ (β-amyloid) peptides, neuronal neurofibrillary tangles (NFTs), sustained neuroinflammation, and synaptic degeneration. The elevated frequency of AD cases and its proclivity to manifest at a younger age present a pressing challenge in the quest for novel therapeutic interventions. Numerous investigations have substantiated the involvement of C/EBPβ in the progression of AD pathology, thus indicating its potential as a therapeutic target for AD treatment. AIMS: Several studies have demonstrated an elevation in the expression level of C/EBPβ among individuals afflicted with AD. Consequently, this review predominantly delves into the association between C/EBPβ expression and the pathological progression of Alzheimer's disease, elucidating its underlying molecular mechanism, and pointing out the possibility that C/EBPβ can be a new therapeutic target for AD. METHODS: A systematic literature search was performed across multiple databases, including PubMed, Google Scholar, and so on, utilizing predetermined keywords and MeSH terms, without temporal constraints. The inclusion criteria encompassed diverse study designs, such as experimental, case-control, and cohort studies, restricted to publications in the English language, while conference abstracts and unpublished sources were excluded. RESU
IMPORTANCE: Baseline cerebral microbleeds (CMBs) and APOE ε4 allele copy number are important risk factors for amyloid-related imaging abnormalities in patients with Alzheimer disease (AD) receiving therapies to lower amyloid-β plaque levels. OBJECTIVE: To provide prevalence estimates of any, no more than 4, or fewer than 2 CMBs in association with amyloid status, APOE ε4 copy number, and age. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study used data included in the Amyloid Biomarker Study data pooling initiative (January 1, 2012, to the present [data collection is ongoing]). Data from 15 research and memory clinic studies were pooled and harmonized. Participants included individuals for whom data on age, cognitive status, amyloid status, and presence of CMBs were available. Data were analyzed from October 22, 2023, to April 26, 2024. MAIN OUTCOMES AND MEASURES: The main outcomes were age, cognitive status, amyloid status and presence, location, and number of CMBs. Presence of amyloid pathology was determined based on 42 amino acid-long form of amyloid-β peptide (Aβ42) levels in cerebrospinal fluid or on amyloid-positron emission tomography. Presence and, in a subset, location (lobar vs deep) and number of CMBs were determined on magnetic resonance imaging (locally with visual rating). RESULTS: Among 4080 participants included in the analysis, the mean (SD) age was 66.5 (8.9) years, and 2241 (54.9%) were female. A total of 2973 participants had no cognitive impa
✗ Opposing Evidence 10
Among the LDL receptor (LDLR) family members, the roles of LDLR-related protein (LRP)1 in the pathogenesis of Alzheimer's disease (AD), especially late-onset AD, have been the most studied by genetic, neuropathological, and biomarker analyses (clinical studies) or cellular and animal model systems (preclinical studies) over the last 25 years. Although there are some conflicting reports, accumulating evidence from preclinical studies indicates that LRP1 not only regulates the metabolism of amyloid-β peptides (Aβs) in the brain and periphery, but also maintains brain homeostasis, impairment of which likely contributes to AD development in Aβ-independent manners. Several preclinical studies have also demonstrated an involvement of LRP1 in regulating the pathogenic role of apoE, whose gene is the strongest genetic risk factor for AD. Nonetheless, evidence from clinical studies is not sufficient to conclude how LRP1 contributes to AD development. Thus, despite very promising results from preclinical studies, the role of LRP1 in AD pathogenesis remains to be further clarified. In this review, we discuss the potential mechanisms underlying how LRP1 affects AD pathogenesis through Aβ-dependent and -independent pathways by reviewing both clinical and preclinical studies. We also discuss potential therapeutic strategies for AD by targeting LRP1.
The low-density lipoprotein receptor (LDLR) gene family includes LDLR, very LDLR, and LDL receptor-related proteins (LRPs) such as LRP1, LRP1b (aka LRP-DIT), LRP2 (aka megalin), LRP4, and LRP5/6, and LRP8 (aka ApoER2). LDLR family members constitute a class of closely related multifunctional, transmembrane receptors, with diverse functions, from embryonic development to cancer, lipid metabolism, and cardiovascular homeostasis. While LDLR family members have been studied extensively in the systemic circulation in the context of atherosclerosis, their roles in pulmonary arterial hypertension (PAH) are understudied and largely unknown. Endothelial dysfunction, tissue infiltration of monocytes, and proliferation of pulmonary artery smooth muscle cells are hallmarks of PAH, leading to vascular remodeling, obliteration, increased pulmonary vascular resistance, heart failure, and death. LDLR family members are entangled with the aforementioned detrimental processes by controlling many pathways that are dysregulated in PAH; these include lipid metabolism and oxidation, but also platelet-derived growth factor, transforming growth factor β1, Wnt, apolipoprotein E, bone morpohogenetic proteins, and peroxisome proliferator-activated receptor gamma. In this paper, we discuss the current knowledge on LDLR family members in PAH. We also review mechanisms and drugs discovered in biological contexts and diseases other than PAH that are likely very relevant in the hypertensive pulmonary vascul
Apolipoprotein E controls Dectin-1-dependent development of monocyte-derived alveolar macrophages upon pulmona… MEDIUM▼
The lung is constantly exposed to the outside world and optimal adaptation of immune responses is crucial for efficient pathogen clearance. However, mechanisms that lead to lung-associated macrophages' functional and developmental adaptation remain elusive. To reveal such mechanisms, we developed a reductionist model of environmental intranasal β-glucan exposure, allowing for the detailed interrogation of molecular mechanisms of pulmonary macrophage adaptation. Employing single-cell transcriptomics, high-dimensional imaging and flow cytometric characterization paired with in vivo and ex vivo challenge models, we reveal that pulmonary low-grade inflammation results in the development of apolipoprotein E (ApoE)-dependent monocyte-derived alveolar macrophages (ApoE+CD11b+ AMs). ApoE+CD11b+ AMs expressed high levels of CD11b, ApoE, Gpnmb and Ccl6, were glycolytic, highly phagocytic and produced large amounts of interleukin-6 upon restimulation. Functional differences were cell intrinsic, and myeloid cell-specific ApoE ablation inhibited Ly6c+ monocyte to ApoE+CD11b+ AM differentiation dependent on macrophage colony-stimulating factor secretion, promoting ApoE+CD11b+ AM cell death and thus impeding ApoE+CD11b+ AM maintenance. In vivo, β-glucan-elicited ApoE+CD11b+ AMs limited the bacterial burden of Legionella pneumophilia after infection and improved the disease outcome in vivo and ex vivo in a murine lung fibrosis model. Collectively these data identify ApoE+CD11b+ AMs generated
The LDL receptor gene family constitutes a class of structurally closely related cell surface receptors fulfilling diverse functions in different organs, tissues, and cell types. The LDL receptor is the prototype of this family, which also includes the VLDLR, ApoER2/LRP8, LRP1 and LRP1B, as well as Megalin/GP330, SorLA/LR11, LRP5, LRP6 and MEGF7. Recently several lines of evidence have positioned the LDL receptor gene family as one of the key players in Alzheimer's disease (AD) research. Initially this receptor family was of high interest due to its key function in cholesterol/apolipoprotein E (ApoE) uptake, with the epsilon4 allele of ApoE as the strongest genetic risk factor for late-onset AD. It has been established that the cholesterol metabolism of the cell has a strong impact on the production of Abeta, the major component of the plaques found in the brain of AD-patients. The original report that soluble amyloid precursor protein (APP) containing the kunitz proteinase inhibitor (KPI) domain might act as a ligand for LRP1 led to a complex investigation of the interaction of both proteins and their potential function in AD development. Meanwhile, it has been demonstrated that LRP1 might bind to APP independent of the KPI domain in APP. This APP - LRP1 interaction is facilitated through a trimeric complex of APP-FE65-LRP1, which has a functional role in APP processing. Along with LRP1, APP is transported from the early secretory compartments to the cell surface and subsequ
Pancreatic cancer's substantial impact on cancer-related mortality, responsible for 8% of cancer deaths and ranking fourth in the US, persists despite advancements, with a five-year relative survival rate of only 11%. Forecasts predict a 70% surge in new cases and a 72% increase in global pancreatic cancer-related deaths by 2040. This review explores the intrinsic metabolic reprogramming of pancreatic cancer, focusing on the mevalonate pathway, including cholesterol biosynthesis, transportation, targeting strategies, and clinical studies. The mevalonate pathway, central to cellular metabolism, significantly shapes pancreatic cancer progression. Acetyl coenzyme A (Acetyl-CoA) serves a dual role in fatty acid and cholesterol biosynthesis, fueling acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) development. Enzymes, including acetoacetyl-CoA thiolase, 3-hydroxy-3methylglutaryl-CoA (HMG-CoA) synthase, and HMG-CoA reductase, are key enzymes in pancreatic cancer. Inhibiting HMG-CoA reductase, e.g., by using statins, shows promise in delaying PanIN progression and impeding pancreatic cancer. Dysregulation of cholesterol modification, uptake, and transport significantly impacts tumor progression, with Sterol O-acyltransferase 1 (SOAT1) driving cholesterol ester (CE) accumulation and disrupted low-density lipoprotein receptor (LDLR) expression contributing to cancer recurrence. Apolipoprotein E (ApoE) expression in tumor stroma influences immune supp
Rationale: Calcific aortic valve disease (CAVD) is a progressive disorder characterized by aortic valve (AV) calcification and fibrosis. Despite advances in our understanding of CAVD pathogenesis, no drug has proven effective in preventing AV calcification. The aim of this study was to identify the key pathogenic genes in CAVD and elucidate mechanisms that may guide development of new targeted therapies. Methods: A CAVD model was established in ApoE-/- mice by administering a high-cholesterol diet for 24 weeks. An adeno-associated virus was used to induce alpha-1-microglobulin/bikunin precursor (AMBP) overexpression. RNA sequencing, quantitative real-time polymerase chain reaction, western blotting, immunofluorescence, histopathology, and echocardiography were performed to assess AV function. The mechanism of interaction between AMBP and four-and-a-half LIM domain protein 3 (FHL3) was explored using bioinformatics analyses, co-immunoprecipitation, and AlphaFold3-based simulations of crystal structures. Results: RNA sequencing identified AMBP as a key regulator of CAVD. AMBP was increased in calcified AV from CAVD patients and high cholesterol diet (HCD)-induced ApoE-/- mice. In vivo, AMBP overexpression significantly reduced HCD-induced AV calcification and fibrosis. In vitro, AMBP knockdown elevated osteogenic markers, RUNX2 and OSTERIX, and promoted calcium deposition in valvular interstitial cells induced by osteogenic medium (OM), whereas AMBP overexpression reversed thes
Apolipoprotein E (APOE) is the major lipid transport protein in the brain. Produced primarily by astrocytes and microglia, it delivers cholesterol and other lipids for membrane repair, synaptic maintenance, and immune regulation. Through interactions with specific lipid receptors, APOE maintains neuronal and vascular health. The APOE ε4 allele (APOE4), carried by approximately one-quarter of the population, has an altered protein conformation, which reduces lipid transport efficiency and modifies receptor binding. These changes disrupt lipid homeostasis, increase risk of chronic unresolved neuroinflammation and vascular inflammation, and cause breakdown of the blood-brain barrier (BBB), thus increasing neuronal vulnerability to disease pathology and elevating risk for Alzheimer's disease (AD). In this review, we organize the effects of APOE4 into three interconnected "hits" that modulate disease progression: disrupted lipid handling, neurovascular inflammation, and neuronal dysfunction. These interconnected hits help explain why amyloid- and tau-directed therapies alone have modest success in treating AD, particularly in APOE4 carriers. We review emerging APOE-related therapeutic strategies designed to address these mechanisms directly, including structure correctors to restore normal protein folding, agents that enhance lipidation and receptor-mediated lipid transport, approaches that modulate downstream inflammatory responses, and gene therapies aimed at isoform switching o
INTRODUCTION: SKYLINE was a secondary prevention study that used blood-based biomarker (BBBM) pre-screening to screen out participants with a low likelihood of amyloid positivity by positron emission tomography (PET) or cerebrospinal fluid (CSF) testing. METHODS: This retrospective analysis used data from SKYLINE (ClinicalTrials.gov: NCT05256134; terminated prematurely) and the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) study to compare predicted and actual clinical performance characteristics of various biomarker combinations using prototype Elecsys® plasma immunoassays (Roche Diagnostics International Ltd, Rotkreuz, Switzerland). RESULTS: In >3500 participants screened in SKYLINE, tau phosphorylated at threonine 181 (pTau181) and apolipoprotein E4 protein (ApoE4p) was the highest-performing BBBM combination. Actual clinical performance of the BBBM pre-screening in SKYLINE was similar to predictions based on A4 in terms of screen-out rate, positive predictive value, and 1-negative predictive value. DISCUSSION: BBBM pre-screening in SKYLINE using prototype plasma pTau181 and ApoE4p immunoassays effectively alleviated participant burden by avoiding unnecessary PET or CSF testing. HIGHLIGHTS: We compared blood-based biomarker (BBBM) performance in SKYLINE and Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4). Pre-screening improved amyloid positivity (defined by positron emission tomography/cerebrospinal fluid) screen failure rate. Tau phosphorylated at threo
OBJECTIVE: We tested biweekly infusions of IV immunoglobulin (IVIg) as a possible treatment for mild to moderate Alzheimer disease (AD) dementia. METHODS: In a phase 3, double-blind, placebo-controlled trial, we randomly assigned 390 participants with mild to moderate AD to receive placebo (low-dose albumin) or IVIg (Gammagard Liquid; Baxalta, Bannockburn, IL) administered IV at doses of 0.2 or 0.4 g/kg every 2 weeks for 18 months. The primary cognitive outcome was change from baseline to 18 months on the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale; the primary functional outcome was 18-month change on the Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory. Safety and tolerability data, as well as serial MRIs and plasma samples, were collected throughout the study from all enrolled participants. RESULTS: No beneficial effects were observed in the dual primary outcome measures for the 2 IVIg doses tested. Significant decreases in plasma Aβ42 (but not Aβ40) levels were observed in IVIg-treated participants. Analysis of safety data showed no difference between IVIg and placebo in terms of the rate of occurrence of amyloid-related imaging abnormalities (brain edema or microhemorrhage). IVIg-treated participants had more systemic reactions (chills, rashes) but fewer respiratory infections than participants receiving placebo. CONCLUSIONS: Participants with mild to moderate AD showed good tolerability of treatment with low-dose huma
The Diamant Alpin Dialysis cohort study: clinico-biological characteristics and cardiovascular genetic risk pr… MEDIUM▼
BACKGROUND: Clinical and therapeutic characteristics of chronic dialysis patients vary widely at national and/or regional levels. Their increased cardiovascular (CV) mortality is not explained by traditional cardiovascular disease (CVD) risk factors only. Therefore, this study aimed to investigate and compare the characteristics of patients starting dialysis in a homogeneous Alpin region and possibly to identify new biological parameters (phenotypes or genotypes), which eould be responsible for the increased CVD seen in end-stage renal disease (ESRD) patients. METHODS: A cohort of 279 non-selected consecutive patients entering a dialysis program was prospectively investigated in eight centers of three adjacent regions in France, Italy and Switzerland. In addition to the usual demographic, clinical and biological data, we analyzed at study entry the blood levels of homocysteine, lipoprotein(a) (Lp(a)) and antioxidized low density lipoprotein (LDL) antibodies, vitamin B12 status, Lp(a) and haptoglobin phenotypes, methylenetetrahydrofolate reductase (MTHFR), angiotensin-converting enzyme (ACE), allele epsilon E4 of apolipoprotein (ApoE4) and plasminogen activator inhibitor-1 (PAI-1) genetic polymorphism. RESULTS: At entry, 90.3% of patients were hypertensive, 30% had type 2 diabetes mellitus and 17.6% were current smokers; 42% of patients had already experienced at least one CV event: peripheral artery disease (26% of the cohort), coronary artery disease (22%) or ischemic cerebr
🧬 Theorist Proposes novel mechanisms and generates creative hypotheses ▼
Here are 7 novel therapeutic hypotheses targeting blood-brain barrier penetrance for antibody therapeutics:
1. Dual-Domain Antibodies with Engineered Fc-FcRn Affinity Modulation
Description: Engineer anti-amyloid antibodies with pH-dependent FcRn binding domains that enhance transcytosis through brain endothelial cells. Modified Fc regions would have increased affinity at acidic pH (endosomal) but reduced affinity at physiological pH, promoting directional transport and extended CNS residence time.
Target: FcRn (FCGRT) receptor and engineered Fc domains
Supporting Evidence:
🔍 Skeptic Identifies weaknesses, alternative explanations, and methodological concerns ▼
I'll provide a rigorous critique of each hypothesis, focusing on scientific weaknesses and gaps in evidence.
1. Dual-Domain Antibodies with Engineered Fc-FcRn Affinity Modulation
Specific Weaknesses:
- The 20% figure for FcRn-mediated BBB transcytosis is likely overestimated; more recent studies suggest <5% (Bohrmann et al., 2012)
- pH-dependent modifications may compromise antibody stability and antigen binding affinity
- No consideration of species differences in FcRn expression patterns between rodents and humans
- Ignores that increased CNS residence time could exacerbate neuroinf
🎯 Domain Expert Assesses practical feasibility, druggability, and clinical translation ▼
PRACTICAL FEASIBILITY ASSESSMENT
I'll assess each hypothesis through a drug development lens, focusing on druggability, existing competitive landscape, and practical implementation challenges.
1. Dual-Domain Antibodies with Engineered Fc-FcRn Affinity Modulation
Druggability Assessment: MODERATE
- Target Class: Established (protein-protein interaction modification)
- Chemical Matter: Antibody engineering via amino acid substitutions in Fc domain
- Precedent: Multiple FDA-approved Fc-engineered antibodies (rituximab variants, etc.)
Existing Compounds/Clini
⚖ Synthesizer Integrates perspectives and produces final ranked assessments ▼
Price History
| Event | Price | Change | Source | Time | |
|---|---|---|---|---|---|
| 📄 | New Evidence | $0.525 | ▲ 0.7% | evidence_batch_update | 2026-04-13 02:18 |
| 📄 | New Evidence | $0.521 | ▲ 2.3% | evidence_batch_update | 2026-04-13 02:18 |
| ⚖ | Recalibrated | $0.509 | ▼ 0.4% | 2026-04-12 10:15 | |
| ⚖ | Recalibrated | $0.511 | ▼ 2.0% | 2026-04-12 05:13 | |
| ⚖ | Recalibrated | $0.522 | ▼ 1.1% | 2026-04-10 15:58 | |
| ⚖ | Recalibrated | $0.528 | ▲ 1.3% | 2026-04-10 15:53 | |
| ⚖ | Recalibrated | $0.521 | ▲ 1.5% | 2026-04-08 18:39 | |
| ⚖ | Recalibrated | $0.513 | ▲ 4.4% | 2026-04-06 04:04 | |
| ⚖ | Recalibrated | $0.491 | ▼ 0.6% | 2026-04-04 16:38 | |
| ⚖ | Recalibrated | $0.494 | ▲ 2.4% | 2026-04-04 16:02 | |
| 📄 | New Evidence | $0.482 | ▲ 1.5% | evidence_batch_update | 2026-04-04 09:08 |
| ⚖ | Recalibrated | $0.475 | ▼ 0.5% | 2026-04-04 01:39 | |
| ⚖ | Recalibrated | $0.478 | ▼ 6.6% | 2026-04-03 23:46 | |
| ⚖ | Recalibrated | $0.512 | ▲ 5.6% | 2026-04-02 21:55 | |
| ⚖ | Recalibrated | $0.485 | ▲ 16.2% | market_recalibrate | 2026-04-02 19:14 |
Clinical Trials (5) Relevance: 44%
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Highest Phase
📚 Cited Papers (50)
📓 Linked Notebooks (1)
Wiki Pages
KG Entities (61)
Dependency Graph (3 upstream, 3 downstream)
Linked Experiments (8)
Related Hypotheses
Estimated Development
🧪 Falsifiable Predictions (4)
Knowledge Subgraph (245 edges)
associated with (15)
co associated with (21)
controls (1)
encodes (10)
enhances (1)
facilitates (1)
implicated in (7)
mediates (3)
modulates (1)
participates in (13)
promoted: Dual-Domain Antibodies with Engineered Fc-FcRn Affinity Modulation (1)
regulates (1)
targets (1)
treats (1)
Mechanism Pathway for APOE, LRP1, LDLR
Molecular pathway showing key causal relationships underlying this hypothesis
graph TD
APOE__LRP1__LDLR["APOE, LRP1, LDLR"] -->|associated with| neurodegeneration["neurodegeneration"]
APOE__LRP1__LDLR_1["APOE, LRP1, LDLR"] -->|co associated with| AQP4["AQP4"]
APOE__LRP1__LDLR_2["APOE, LRP1, LDLR"] -->|co associated with| CLDN5__OCLN["CLDN5, OCLN"]
APOE__LRP1__LDLR_3["APOE, LRP1, LDLR"] -->|co associated with| FCGRT["FCGRT"]
APOE__LRP1__LDLR_4["APOE, LRP1, LDLR"] -->|co associated with| LRP1__MTNR1A__MTNR1B["LRP1, MTNR1A, MTNR1B"]
APOE__LRP1__LDLR_5["APOE, LRP1, LDLR"] -->|co associated with| TFR1["TFR1"]
APOE__LRP1__LDLR_6["APOE, LRP1, LDLR"] -->|co associated with| TFR1__LRP1__CAV1__ABCB1["TFR1, LRP1, CAV1, ABCB1"]
style APOE__LRP1__LDLR fill:#ce93d8,stroke:#333,color:#000
style neurodegeneration fill:#ef5350,stroke:#333,color:#000
style APOE__LRP1__LDLR_1 fill:#ce93d8,stroke:#333,color:#000
style AQP4 fill:#ce93d8,stroke:#333,color:#000
style APOE__LRP1__LDLR_2 fill:#ce93d8,stroke:#333,color:#000
style CLDN5__OCLN fill:#ce93d8,stroke:#333,color:#000
style APOE__LRP1__LDLR_3 fill:#ce93d8,stroke:#333,color:#000
style FCGRT fill:#ce93d8,stroke:#333,color:#000
style APOE__LRP1__LDLR_4 fill:#ce93d8,stroke:#333,color:#000
style LRP1__MTNR1A__MTNR1B fill:#ce93d8,stroke:#333,color:#000
style APOE__LRP1__LDLR_5 fill:#ce93d8,stroke:#333,color:#000
style TFR1 fill:#ce93d8,stroke:#333,color:#000
style APOE__LRP1__LDLR_6 fill:#ce93d8,stroke:#333,color:#000
style TFR1__LRP1__CAV1__ABCB1 fill:#ce93d8,stroke:#333,color:#000
3D Protein Structure
🧬 APOE — PDB 2L7B Click to expand 3D viewer
Source Analysis
Blood-brain barrier transport mechanisms for antibody therapeutics
neurodegeneration | 2026-04-01 | completed