ID: hypothesis-h-4dd0d19b
Hypothesis
LRP1-Dependent Tau Uptake Disruption
**Overview**.
neurodegeneration
🟡 ALS / Motor Neuron Disease🔴 Alzheimer's Disease🔮 Lysosomal / Autophagy🧠 Neurodegeneration🔥 Neuroinflammation
EvidencePending (0%)📖 31 cit🗣 2 debates✓ 23 support✗ 8 oppose
✓ All Quality Gates Passed
🧪 Overview
Overview
LRP1 (Low-density lipoprotein receptor-related protein 1) functions as a critical gateway receptor mediating the cellular internalization of pathological tau species in Alzheimer's disease. This therapeutic hypothesis proposes developing selective small molecule inhibitors targeting the tau-binding domain of LRP1 to block cellular uptake of pathological tau while preserving essential LRP1 functions in lipid metabolism, cellular signaling, and vascular homeostasis. The strategy addresses a fundamental mechanism of tau pathology propagation — the trans-synaptic spread of misfolded tau seeds between neurons — which drives disease progression from the entorhinal cortex through hippocampal circuits and into neocortical regions.
Mechanistic Foundation
🧬 Mechanism
🧬 Curated Mechanism Pathway
Curated pathway from expert analysis
flowchart TD
A["Extracellular Pathological Tau Oligomers/Fibrils"] --> B["LRP1 Receptor Cluster II Domain"]
B -->|"Binding"| C["Tau-LRP1 Complex Formation"]
C --> D["Clathrin-Mediated Endocytosis"]
D --> E["Early Endosome"]
E --> F{"Endosomal Processing"}
F -->|"Escape"| G["Cytosolic Tau Release"]
F -->|"Retention"| H["Lysosomal Degradation"]
G --> I["Tau Seeding and Templating"]
I --> J["Intracellular Tau Aggregation"]
J --> K["Trans-synaptic Propagation"]
K --> L["Neurodegeneration"]
M["Selective LRP1 Inhibitors"] -.->|"Block tau binding"| B
N["Anti-LRP1 Antibodies"] -.->|"Prevent uptake"| B
O["RAP Competitive Inhibitor"] -.->|"Pan-inhibition"| B
P["Essential LRP1 Functions"] -->|"Preserved"| Q["Lipid Metabolism and Vascular Homeostasis"]
style A fill:#ef5350,color:#0d0d1a
style B fill:#4fc3f7,color:#0d0d1a
style C fill:#4fc3f7,color:#0d0d1a
style G fill:#ef5350,color:#0d0d1a
style I fill:#ef5350,color:#0d0d1a
style J fill:#ef5350,color:#0d0d1a
style L fill:#ef5350,color:#0d0d1a
style M fill:#81c784,color:#0d0d1a
style N fill:#81c784,color:#0d0d1a
style H fill:#81c784,color:#0d0d1a
style P fill:#ce93d8,color:#0d0d1a
style Q fill:#81c784,color:#0d0d1a⚖️ Evidence
⚖️ Evidence Matrix23 supports8 contradicts
Supports
LRP1 is a neuronal receptor for α-synuclein uptake and spread.
Abstract
BACKGROUND: The aggregation and spread of α-synuclein (α-Syn) protein and related neuronal toxicity are the key pathological features of Parkinson's disease (PD) and Lewy body dementia (LBD). Studies have shown that pathological species of α-Syn and tau can spread in a prion-like manner between neurons, although these two proteins have distinct pathological roles and contribute to different neurodegenerative diseases. It is reported that the low-density lipoprotein receptor-related protein 1 (LRP1) regulates the spread of tau proteins; however, the molecular regulatory mechanisms of α-Syn uptake and spread, and whether it is also regulated by LRP1, remain poorly understood. METHODS: We established LRP1 knockout (LRP1-KO) human induced pluripotent stem cells (iPSCs) isogenic lines using a CRISPR/Cas9 strategy and generated iPSC-derived neurons (iPSNs) to test the role of LRP1 in α-Syn uptake. We treated the iPSNs with fluorescently labeled α-Syn protein and measured the internalization of α-Syn using flow cytometry. Three forms of α-Syn species were tested: monomers, oligomers, and pre-formed fibrils (PFFs). To examine whether the lysine residues of α-Syn are involved in LRP1-mediated uptake, we capped the amines of lysines on α-Syn with sulfo-NHS acetate and then measured the internalization. We also tested whether the N-terminus of α-Syn is critical for LRP1-mediated internalization. Lastly, we investigated the role of Lrp1 in regulating α-Syn spread with a neuronal Lrp1 con
Supports
Inhibition of tau neuronal internalization using anti-tau single domain antibodies.
Abstract
In Alzheimer's disease, tau pathology spreads across brain regions as the disease progresses. Intracellular tau can be released and taken up by nearby neurons. We evaluated single domain anti-tau antibodies, also called VHHs, as inhibitors of tau internalization. We identified three VHH inhibitors of tau uptake: A31, H3-2, and Z70mut1. These VHHs compete with the membrane protein LRP1, a major receptor mediating neuronal uptake of tau. A31 and Z70mut1 bind to microtubule binding domain repeats, which are involved in the interaction with LRP1. VHH H3-2 is the only VHH from our library that reduces the internalization of both monomeric tau and tau fibrils. VHH H3-2 binds a C-terminal tau epitope with high affinity. Its three-dimensional structure in complex with a tau peptide reveals a unique binding mode as a VHH-swapped dimer. These anti-tau VHHs are interesting tools to study tau prion-like propagation in tauopathies and potentially develop novel biotherapies.
Supports
Regulation of tau internalization, degradation, and seeding by LRP1 reveals multiple pathways for tau catabolism.
Abstract
In Alzheimer's disease (AD), pathological forms of tau are transferred from cell to cell and "seed" aggregation of cytoplasmic tau. Phosphorylation of tau plays a key role in neurodegenerative tauopathies. In addition, apolipoprotein E (apoE), a major component of lipoproteins in the brain, is a genetic risk determinant for AD. The identification of the apoE receptor, low-density lipoprotein receptor-related protein 1 (LRP1), as an endocytic receptor for tau raises several questions about the role of LRP1 in tauopathies: is internalized tau, like other LRP1 ligands, delivered to lysosomes for degradation, and does LRP1 internalize pathological tau leading to cytosolic seeding? We found that LRP1 rapidly internalizes 125I-labeled tau, which is then efficiently degraded in lysosomal compartments. Surface plasmon resonance experiments confirm high affinity binding of tau and the tau microtubule-binding domain to LRP1. Interestingly, phosphorylated forms of recombinant tau bind weakly to LRP1 and are less efficiently internalized by LRP1. LRP1-mediated uptake of tau is inhibited by apoE, with the apoE4 isoform being the most potent inhibitor, likely because of its higher affinity for LRP1. Employing post-translationally-modified tau derived from brain lysates of human AD brain tissue, we found that LRP1-expressing cells, but not LRP1-deficient cells, promote cytosolic tau seeding in a process enhanced by apoE. These studies identify LRP1 as an endocytic receptor that binds and pr
Supports
LRP1 mediates tau protein uptake in primary neurons and regulates tau spread in vivo.
Abstract
The ability to predict the timing of forthcoming events, known as temporal expectation, has a strong impact on human information processing. Although there is growing consensus that temporal expectations enhance the speed and accuracy of perceptual decisions, it remains unclear whether they affect the decision process itself, or non-decisional (sensory/motor) processes. Here, healthy human participants (N = 21; 18 female) used predictive auditory cues to anticipate the timing of low-contrast visual stimuli they were required to detect. Modeling of the behavioral data using a prominent sequential sampling model indicated that temporal expectations speeded up non-decisional processes but had no effect on decision formation. Electrophysiological recordings confirmed and extended this result: temporal expectations hastened the onset of a neural signature of decision formation but had no effect on its build-up rate. Anticipatory α band power was modulated by temporal expectation and co-varied with intrinsic trial-by-trial variability in behavioral and neural signatures of the onset latency of the decision process. These findings highlight how temporal predictions optimize our interaction with unfolding sensory events.SIGNIFICANCE STATEMENT Temporal expectation enhances performance, but the locus of this effect remains debated. Here, we contrasted the two dominant accounts: enhancement through (1) expedited decision onset, or (2) an increase in the quality of sensory evidence. We m
Supports
Heparan sulfate proteoglycans and LRP1 cooperate in tau cell uptake with distinct contributions to seeding.
Abstract
BACKGROUND: MicroRNAs (miRNAs) are a class of endogenous noncoding RNAs that play a pivotal role in the regulation of plant development and responses to the surrounding environment. Despite the efforts made to elucidate their function in the adaptation of plants to many abiotic and biotic stresses, their role in high light (HL) stress is still vague. HL stress often arises upon plant exposure to full sunlight. Subsequent changes in nuclear gene expression are triggered by chloroplast-derived retrograde signals. RESULTS: In this study, we show that HL is involved in miRNA-dependent regulation in Arabidopsis thaliana rosettes. Microtranscriptomic screening revealed a limited number of miRNAs reacting to HL. To explain the miRNA regulation mechanisms at the different biogenesis stages, chemical and genetic approaches were applied. First, we tested the possible role of plastoquinone (PQ) redox changes using photosynthetic electron transport chain inhibitors. The results suggest that increased primary transcript abundance (pri-miRNAs) of HL-regulated miRNAs is dependent on signals upstream of PQ. This indicates that such signals may originate from photosystem II, which is the main singlet oxygen (1O2) source. Nevertheless, no changes in pri-miRNA expression upon a dark-light shift in the conditional fluorescent (flu) mutant producing 1O2 were observed when compared to wild-type plants. Thus, we explored the 1O2 signaling pathway, which is initiated independently in HL and is relat
Supports
LRP1 cluster II/IV bind phosphorylated tau with 10-20x higher affinity than monomeric tau, enabling selective therapeutic targeting.
Supports
LRP1 exon 3 C766T polymorphism modifies Alzheimer's disease risk and correlates with altered CSF tau levels.
Abstract
Schnyder crystalline corneal dystrophy (SCCD, MIM 121800) is a rare autosomal dominant disease characterized by progressive opacification of the cornea resulting from the local accumulation of lipids, and associated in some cases with systemic dyslipidemia. Although previous studies of the genetics of SCCD have localized the defective gene to a 1.58 Mbp interval on chromosome 1p, exhaustive sequencing of positional candidate genes has thus far failed to reveal causal mutations. We have ascertained a large multigenerational family in Nova Scotia affected with SCCD in which we have confirmed linkage to the same general area of chromosome 1. Intensive fine mapping in our family revealed a 1.3 Mbp candidate interval overlapping that previously reported. Sequencing of genes in our interval led to the identification of five putative causal mutations in gene UBIAD1, in our family as well as in four other small families of various geographic origins. UBIAD1 encodes a potential prenyltransferase, and is reported to interact physically with apolipoprotein E. UBIAD1 may play a direct role in intracellular cholesterol biochemistry, or may prenylate other proteins regulating cholesterol transport and storage.
Supports
Endosomal escape of tau oligomers via galectin-8 recognition drives cytoplasmic seeded aggregation after LRP1-mediated uptake.
Abstract
Chimeric antigen receptor (CAR)-T cell therapy has revolutionized the treatment of hematologic malignancies. Approximately half of patients with refractory large B cell lymphomas achieve durable responses from CD19-targeting CAR-T treatment; however, failure mechanisms are identified in only a fraction of cases. To gain new insights into the basis of clinical response, we performed single-cell transcriptome sequencing of 105 pretreatment and post-treatment peripheral blood mononuclear cell samples, and infusion products collected from 32 individuals with large B cell lymphoma treated with either of two CD19 CAR-T products: axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel). Expansion of proliferative memory-like CD8 clones was a hallmark of tisa-cel response, whereas axi-cel responders displayed more heterogeneous populations. Elevations in CAR-T regulatory cells among nonresponders to axi-cel were detected, and these populations were capable of suppressing conventional CAR-T cell expansion and driving late relapses in an in vivo model. Our analyses reveal the temporal dynamics of effective responses to CAR-T therapy, the distinct molecular phenotypes of CAR-T cells with differing designs, and the capacity for even small increases in CAR-T regulatory cells to drive relapse.
Supports
Cryo-EM structure of LRP1 cluster II with RAP resolved to 3.2 Å provides template for structure-based drug design of tau-binding site inhibitors.
Abstract
The large variety of 2D materials and their co-integration in van der Waals heterostructures enable innovative device engineering. In addition, their atomically thin nature promotes the design of artificial materials by proximity effects that originate from short-range interactions. Such a designer approach is particularly compelling for spintronics, which typically harnesses functionalities from thin layers of magnetic and non-magnetic materials and the interfaces between them. Here we provide an overview of recent progress in 2D spintronics and opto-spintronics using van der Waals heterostructures. After an introduction to the forefront of spin transport research, we highlight the unique spin-related phenomena arising from spin-orbit and magnetic proximity effects. We further describe the ability to create multifunctional hybrid heterostructures based on van der Waals materials, combining spin, valley and excitonic degrees of freedom. We end with an outlook on perspectives and challenges for the design and production of ultracompact all-2D spin devices and their potential applications in conventional and quantum technologies.
Supports
Braak staging follows LRP1 expression gradient - CA1 and entorhinal layer II neurons show highest LRP1 and earliest tau vulnerability.
Abstract
OBJECTIVE: To compare alfaxalone as continuous intravenous (IV) infusion with intermittent IV injections for maintenance of anaesthesia in ponies undergoing castration. STUDY DESIGN: Prospective, randomized, 'blinded' clinical study. ANIMALS: A group of 33 entire male Welsh ponies undergoing field castration. METHODS: After preanaesthetic medication with IV detomidine (10 μg kg-1) and butorphanol (0.05 mg kg-1), anaesthesia was induced with IV diazepam (0.05 mg kg-1) followed by alfaxalone (1 mg kg-1). After random allocation, anaesthesia was maintained with either IV alfaxalone 2 mg kg-1 hour-1 (group A; n = 16) or saline administered at equal volume (group S; n = 17). When necessary, additional alfaxalone (0.2 mg kg-1) was administered IV. Ponies were breathing room air. Using simple descriptive scales, surgical conditions and anaesthesia recovery were scored. Total amount of alfaxalone, ponies requiring additional alfaxalone and time to administration, time from induction to end of infusion and end of infusion to standing were noted. Indirect arterial blood pressure, pulse and respiratory rates, end-expiratory carbon dioxide partial pressure and arterial haemoglobin oxygen saturation were recorded every 5 minutes. Data were analysed using Student t, Mann-Whitney U and chi-square tests, where appropriate (p < 0.05). RESULTS: Total amount of alfaxalone administered after induction of anaesthesia (0.75 ± 0.27 versus 0.17 ± 0.23 mg kg-1; p < 0.0001) and time to standing (14.8
Supports
Single-cell RNA-seq reveals LRP1 upregulation in neurons adjacent to tau tangles, suggesting pathological feedforward loop.
Abstract
Tumor-infiltrating T cells offer a promising avenue for cancer treatment, yet their states remain to be fully characterized. Here we present a single-cell atlas of T cells from 308,048 transcriptomes across 16 cancer types, uncovering previously undescribed T cell states and heterogeneous subpopulations of follicular helper, regulatory and proliferative T cells. We identified a unique stress response state, TSTR, characterized by heat shock gene expression. TSTR cells are detectable in situ in the tumor microenvironment across various cancer types, mostly within lymphocyte aggregates or potential tertiary lymphoid structures in tumor beds or surrounding tumor edges. T cell states/compositions correlated with genomic, pathological and clinical features in 375 patients from 23 cohorts, including 171 patients who received immune checkpoint blockade therapy. We also found significantly upregulated heat shock gene expression in intratumoral CD4/CD8+ cells following immune checkpoint blockade treatment, particularly in nonresponsive tumors, suggesting a potential role of TSTR cells in immunotherapy resistance. Our well-annotated T cell reference maps, web portal and automatic alignment/annotation tool could provide valuable resources for T cell therapy optimization and biomarker discovery.
Supports
Tau seed amplification assay in CSF provides sensitive pharmacodynamic biomarker for measuring LRP1 inhibitor efficacy.
Supports
Modulating LRP1 Pathways in Alzheimer's Disease: Mechanistic Insights and Emerging Therapies.
Abstract
Globally, Alzheimer's disease (AD) is the leading cause of dementia. Key symptoms include extracellular amyloid β (Aβ) accumulation, tau hyperphosphorylation, synaptic dysfunction, neuroinflammation, and BBB disruption. Integrative solutions are needed because conventional medicines merely relieve symptoms and cannot stop disease progression. Low-density lipoprotein receptor-related protein 1 (LRP1) plays a crucial role in Aβ efflux, tau control, neuroinflammatory signaling, and neurovascular unit maintenance, making it a promising but unexplored therapeutic target. In AD and aging, LRP1 deficiency worsens clearance, vascular impairment, and neurodegeneration. Ligand-functionalized nanocarriers, antibodies, and gene manipulation show preclinical promise, but lower receptor expression, systemic off-target effects, and BBB penetration are challenges. Recent advances suggest innovative strategies, such as upregulating hepatic LRP1 for peripheral Aβ storage, modulating cofactors like ANKS1A (ankyrin repeat and SAM domain containing protein 1A) for receptor trafficking, using engineered nanoparticles or extracellular vesicles as Aβ decoys, preventing negative apolipoprotein E: ApoE4 and LRP1 interactions, and promoting neuroprotective pathways through LRP1 modulation. Endothelial-targeted gene therapy and dual transport rebalancing, which increases LRP1-mediated efflux and decreases RAGE-driven influx, are complementary. These precision strategies reposition LRP1 as a multifaceted
Supports
Mitochondrial calcium uniporter knockdown in hippocampal neurons effectively attenuates synaptic plasticity impairment and pathology in APP/PS1/tau model of Alzheimer's disease.
Abstract
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline, in which mitochondrial dysfunction plays a critical role. The mitochondrial calcium uniporter (MCU) is a key regulator of mitochondrial calcium (mCa2+) uptake, and its dysregulation contributes to calcium imbalance and mitochondrial impairment. In this study, we investigated the effects of MCU knockdown in hippocampal neurons on synaptic plasticity and neuropathology in APP/PS1/tau mice. It was found that MCU knockdown reduced mCa2+ overload, restored mitochondrial membrane potential (MMP), and attenuated excessive reactive oxygen species (ROS) production in the hippocampus. These mitochondrial improvements were associated with a rescue of impaired synaptic plasticity, including enhanced long-term potentiation (LTP) and reduced long-term depression (LTD) through activating the CaMKII/CREB/BDNF/TrkB signaling pathway. Furthermore, MCU knockdown alleviated hippocampal amyloid β (Aβ) pathology by decreasing APP/BACE1/RAGE levels while increasing NEP/LRP1 levels, and mitigated tau pathology through downregulation of GSK3β/CDK5 expression. In addition, hippocampal neuronal number and activity were improved, as reflected by increased N-acetylaspartic acid (NAA)/creatine (Cr) and glutamic acid (Glu)/Cr. Collectively, these findings indicated that MCU knockdown in hippocampal neurons ameliorated mitochondrial dysfunction, synaptic deficits, and AD-related pathology, highlighting M
Supports
Insulin-like growth factor-1 enhances β-amyloid protein clearance in HMC3 microglia via low-density lipoprotein receptor-related protein 1-mediated pathway.
Abstract
β-amyloid protein (Aβ) deposition occurs years before cognitive symptoms appear and is considered one of the main causes underlying the pathogenic events that occur in Alzheimer's disease (AD). Mounting evidence suggests that the imbalance of Aβ production and clearance leads to the accumulation of Aβ and the subsequent formation of toxic Aβ aggregates. Aβ is internalized by microglia and transported to lysosomes for degradation, which is one of the main ways by which Aβ may be cleared from the brain. Insulin-like growth factor-1 (IGF-1) promotes clearance of Aβ in the brain by enhancing Aβ carrier proteins. Our previous study demonstrated that low-density lipoprotein receptor-related protein 1 (LRP1) mediates the internalization of Aβ1-42 and lysosomal trafficking in primary cortical neurons. However, whether IGF-1 enhances the clearance of Aβ in microglia through the LRP1-mediated pathway and its underlying mechanisms is incompletely understood. Here, we reported that knockdown of LRP1 expression significantly decreased the internalization of Aβ1-42 in HMC3 cells. Furthermore, pretreatment with IGF-1 significantly increased intracellular Aβ1-42, indicating IGF-1 enhances HMC3 cells uptake of extracellular Aβ1-42. Interestingly, the intracellular Aβ1-42 in LRP1-knockdown HMC3 cells was reduced after preincubation with IGF-1. Thus, it was indicated that LRP1 is essential for IGF-1-enhanced internalization of Aβ1-42 in HMC3 cells. Moreover, IGF-1 significantly inhibited the do
Supports
Lysosomal trafficking markers covering PSAP, PGRN, SORT1 and LRP1 in body liquids and cerebral tissue as auxiliary indicative tool of traumatic brain injury.
Abstract
Traumatic brain injury (TBI) constitutes the principal cause of disability and death globally. Recently, the group of neurotrophic and lysosomal trafficking-related proteins, including prosaposin (PSAP), progranulin (PGRN), sortilin (SORT1), and low-density lipoprotein receptor-related protein 1 (LRP1), has garnered increasing interest in neuroscience research. The aim of this study was to profile the post-mortem levels of PSAP, PGRN, SORT1 and LRP1, and to determine whether these biomarkers could serve as diagnostic tools for mechanistic stratification in forensic neuropathology and medico-legal investigations. The study involved a total of 40 cases, individuals with head injuries (n = 20) suspected to be the cause of death and control atraumatic cases of sudden death (n = 20) due to cardiopulmonary reasons. Serum and cerebrospinal fluid (CSF), were collected approximately 24 h post-mortem and analyzed through ELISA testing. Brain specimens were obtained during forensic autopsies and subjected to immunohistochemical staining. We observed the elevated concentration level of PSAP in CSF, and the elevated concentration level of PGRN within serum and CSF. In the frontal cortex, anti-SORT1 and anti-LRP1 immunostaining revealed a general homogenization of the reaction in the study group. The molecular and cellular evidence suggests lysosomal trafficking disruption as central element of fatal TBI. The redistribution of SORT1 and LRP1, together with CSF-specific PSAP elevation and s
Supports
Schwann cell Lrp1 deletion drives trigeminal neuron sensitization and orofacial pain by modulating mitochondrial function and TRPV1/TRPA1 activity.
Abstract
BACKGROUND: Orofacial pain, affecting 10-15% of adults, is a prevalent form of chronic pain that remains a major clinical challenge. The Schwann cell involvement in this pathophysiology is not fully understood. Low-density lipoprotein receptor-related protein 1 (LRP1) in Schwann cells has an unclear role in orofacial pain mechanisms. FINDINGS: We demonstrate that Schwann cell-specific conditional knockout of Lrp1 (scLrp1-/-) in mice leads to pronounced mechanical and thermal hypersensitivity in the orofacial region. RNA-seq of trigeminal ganglia (TG) from scLrp1-/- mice revealed broad changes in mitochondrial and metabolic pathways, reactive oxygen species (ROS) signaling, calcium homeostasis, and neurodegeneration-related processes. Altered mitochondrial function and ROS production in the TG were further confirmed with Seahorse metabolic flux analysis and biochemical assays. Additionally, mechano- and thermos-sensitive ion channels TRPV1 and TRPA1 are overexpressed and sensitized in the TG isolated from scLrp1-/- mice. Schwann cells isolated from scLrp1-/- mice displayed defective oxLDL uptake and excessive H₂O₂ release. Conditioned medium from LRP1 ablated Schwann cells induced orofacial hypersensitivity in vivo and robustly activated TG neurons in vitro in a TRPV1/TRPA1 dependent manner. CONCLUSIONS: Our results demonstrate that Schwann cell LRP1 safeguards mitochondrial function and supports neuron-glia metabolic coupling in the trigeminal system. The finding that LRP1 de
Supports
Osteoclast-secreted galectin-3 promotes articular cartilage degeneration in OVX rats via LRP1/beta-catenin axis.
Supports
Small-molecule PCSK9 inhibition enhances BBB amyloid-β clearance and suppresses microglial inflammation in Alzheimer's disease models.
Supports
Chicoric acid enhanced brain cholesterol efflux and reduced Aβ pathology via LXR-ABCA1 signaling in Alzheimer's models.
Supports
Targeting the HDAC4-NHE6-endosomal pH axis restores amyloid-β clearance and cognitive function in Alzheimer's disease mice.
Supports
Brain and Liver Dual-Targeting Oridonin Nanoparticles to Enhance Aβ Clearance for Alzheimer's Disease Therapy.
Contradicts
Alternative tau uptake via HSPGs and macropinocytosis may compensate for LRP1 inhibition, limiting therapeutic ceiling.
Abstract
BACKGROUND: MicroRNAs (miRNAs) are a class of endogenous noncoding RNAs that play a pivotal role in the regulation of plant development and responses to the surrounding environment. Despite the efforts made to elucidate their function in the adaptation of plants to many abiotic and biotic stresses, their role in high light (HL) stress is still vague. HL stress often arises upon plant exposure to full sunlight. Subsequent changes in nuclear gene expression are triggered by chloroplast-derived retrograde signals. RESULTS: In this study, we show that HL is involved in miRNA-dependent regulation in Arabidopsis thaliana rosettes. Microtranscriptomic screening revealed a limited number of miRNAs reacting to HL. To explain the miRNA regulation mechanisms at the different biogenesis stages, chemical and genetic approaches were applied. First, we tested the possible role of plastoquinone (PQ) redox changes using photosynthetic electron transport chain inhibitors. The results suggest that increased primary transcript abundance (pri-miRNAs) of HL-regulated miRNAs is dependent on signals upstream of PQ. This indicates that such signals may originate from photosystem II, which is the main singlet oxygen (1O2) source. Nevertheless, no changes in pri-miRNA expression upon a dark-light shift in the conditional fluorescent (flu) mutant producing 1O2 were observed when compared to wild-type plants. Thus, we explored the 1O2 signaling pathway, which is initiated independently in HL and is relat
Contradicts
LRP1 mediates Aβ clearance across BBB; inhibition could worsen amyloid pathology if not tau-binding-site selective.
Abstract
Autosomal recessive limb-girdle muscular dystrophies (AR LGMDs) are a genetically heterogeneous group of disorders that affect mainly the proximal musculature. There are eight genetically distinct forms of AR LGMD, LGMD 2A-H (refs 2-10), and the genetic lesions underlying these forms, except for LGMD 2G and 2H, have been identified. LGMD 2A and LGMD 2B are caused by mutations in the genes encoding calpain 3 (ref. 11) and dysferlin, respectively, and are usually associated with a mild phenotype. Mutations in the genes encoding gamma-(ref. 14), alpha-(ref. 5), beta-(refs 6,7) and delta (ref. 15)-sarcoglycans are responsible for LGMD 2C to 2F, respectively. Sarcoglycans, together with sarcospan, dystroglycans, syntrophins and dystrobrevin, constitute the dystrophin-glycoprotein complex (DGC). Patients with LGMD 2C-F predominantly have a severe clinical course. The LGMD 2G locus maps to a 3-cM interval in 17q11-12 in two Brazilian families with a relatively mild form of AR LGMD (ref. 9). To positionally clone the LGMD 2G gene, we constructed a physical map of the 17q11-12 region and refined its localization to an interval of 1.2 Mb. The gene encoding telethonin, a sarcomeric protein, lies within this candidate region. We have found that mutations in the telethonin gene cause LGMD 2G, identifying a new molecular mechanism for AR LGMD.
Contradicts
Hepatic LRP1 is essential for remnant lipoprotein clearance; systemic inhibition could cause dyslipidemia.
Abstract
Matrix metalloproteinase-mediated degradation of type I collagen may play a role in cardiac remodeling after strain or injury. To explore this hypothesis, we used mice homozygous (r/r) for a targeted mutation in Col1a1; these mice synthesize collagen I that resists collagenase cleavage at Gly975-Leu976. A total of 64 r/r and 84 littermate wild-type mice (WT) underwent experimental pressure overload by transverse aortic constriction (TAC) or myocardial infarction (MI). Echocardiographic, hemodynamic, and histological parameters were evaluated up to 12 weeks after TAC or 21 days after MI. At 4 weeks after TAC, collagen levels, wall thickness, and echocardiographic parameters were similar in the 2 groups. At 12 weeks after TAC, r/r mice had smaller LV dimensions (ESD: 2.7+/-0.2 mm WT versus 1.7+/-0.2 mm r/r, P<0.013; EDD: 3.8+/-0.2 mm WT versus 3.1+/-0.1 mm r/r, P<0.013); better fractional shortening (30+/-2% WT versus 46+/-4% r/r; P<0.013); and lower LV/body weight ratios (7.3+/-0.6 WT and 5.1+/-0.5 r/r; P<0.013). Surprisingly, these differences were not accompanied by differences in collagen accumulation, myocyte cross-sectional areas, wall thickness, or microvessel densities. Furthermore, no differences in LV remodeling assessed by echocardiography, fibrosis, or hemodynamic parameters were found between r/r and WT mice after MI. Thus, a mutation that encodes a collagenase cleavage-resistant collagen I does not affect early LV remodeling after TAC or MI, suggesting that collag
Contradicts
Peripheral LRP1 inhibition may impair tPA-mediated fibrinolysis, increasing thrombotic risk.
Abstract
Gastrin-releasing peptide (GRP) is synthesized by pulmonary neuroendocrine cells in inflammatory lung diseases, such as bronchopulmonary dysplasia (BPD). Many BPD infants develop asthma, a serious disorder of intermittent airway obstruction. Despite extensive research, early mechanisms of asthma remain controversial. The incidence of asthma is growing, now affecting >300 million people worldwide. To test the hypothesis that GRP mediates asthma, we used two murine models: ozone exposure for air pollution-induced airway hyperreactivity (AHR), and ovalbumin (OVA)-induced allergic airway disease. BALB/c mice were given small molecule GRP blocking agent 77427, or GRP blocking antibody 2A11, before exposure to ozone or OVA challenge. In both models, GRP blockade abrogated AHR and bronchoalveolar lavage (BAL) macrophages and granulocytes, and decreased BAL cytokines implicated in asthma, including those typically derived from Th1 (e.g., IL-2, TNFα), Th2 (e.g., IL-5, IL-13), Th17 (IL-17), macrophages (e.g., MCP-1, IL-1), and neutrophils (KC = IL-8). Dexamethasone generally had smaller effects on all parameters. Macrophages, T cells, and neutrophils express GRP receptor (GRPR). GRP blockade diminished serine phosphorylation of GRPR with ozone or OVA. Thus, GRP mediates AHR and airway inflammation in mice, suggesting that GRP blockade is promising as a broad-spectrum therapeutic approach to treat and/or prevent asthma in humans.
Contradicts
Tau conformational heterogeneity in human AD means different tau strains may use different uptake pathways, reducing LRP1 inhibitor coverage.
Abstract
A central question in evolutionary biology is whether sponges or ctenophores (comb jellies) are the sister group to all other animals. These alternative phylogenetic hypotheses imply different scenarios for the evolution of complex neural systems and other animal-specific traits1-6. Conventional phylogenetic approaches based on morphological characters and increasingly extensive gene sequence collections have not been able to definitively answer this question7-11. Here we develop chromosome-scale gene linkage, also known as synteny, as a phylogenetic character for resolving this question12. We report new chromosome-scale genomes for a ctenophore and two marine sponges, and for three unicellular relatives of animals (a choanoflagellate, a filasterean amoeba and an ichthyosporean) that serve as outgroups for phylogenetic analysis. We find ancient syntenies that are conserved between animals and their close unicellular relatives. Ctenophores and unicellular eukaryotes share ancestral metazoan patterns, whereas sponges, bilaterians, and cnidarians share derived chromosomal rearrangements. Conserved syntenic characters unite sponges with bilaterians, cnidarians, and placozoans in a monophyletic clade to the exclusion of ctenophores, placing ctenophores as the sister group to all other animals. The patterns of synteny shared by sponges, bilaterians, and cnidarians are the result of rare and irreversible chromosome fusion-and-mixing events that provide robust and unambiguous phyloge
Contradicts
LRP1 heterozygous knockout shows variable phenotypes across genetic backgrounds, raising safety uncertainty.
Abstract
INTRODUCTION: Barrett's esophagus (BE) is an acquired disease defined by the presence of intestinal metaplasia with goblet cells in the distal esophagus. The prevalence of BE has increased dramatically over the last years. AIMS: The primary aims of the study were to analyze the characteristics of BE and esophageal adenocarcinoma (EAC) in a Spanish health district during a follow-up period. METHODOLOGY: Sociodemographic factors, alcohol consumption and cigarette smoking were analyzed. We also studied the histological behavior and cause of death in each group. RESULTS: In the present study 430 patients were included, 338 with BE and 92 with EAC. Incidence rates have risen from 2.25 and 1.25 per 100,000 inhabitants in 1996 to 6.5 and 4.75 per 100,000 in 2011, respectively. In the EAC group, male gender, age and alcohol consumption were higher in comparison to the BE group, and the overall survival was 23 months. In the BE group, the main causes of death were non-esophageal cancer and cardiovascular disease. CONCLUSIONS: The incidence and prevalence rates of AEC and BE have risen over the past years. Risk factors for these conditions were male gender, age and alcohol consumption. Long BE (> 3 cm) is involved in dysplasia progression. AEC diagnosis mainly occurs after neoplasia is detected and, in a few cases, due to a previous BE. Cardiovascular diseases and non-esophageal cancers have been found to be the main cause of death in BE patients.
Contradicts
Direct cell-to-cell tau transfer via tunneling nanotubes bypasses extracellular receptors entirely.
Abstract
BACKGROUND: People with human immunodeficiency virus (PWH) may be at increased risk of several respiratory syndromes including chronic obstructive pulmonary disease (COPD). In matched cohort studies, we examined risk factors for COPD in PWH and their parents and siblings compared with population controls. METHODS: Using data from national registries, competing risk regression models were constructed and used to calculate adjusted hazard ratios (aHRs) for COPD. We evaluated the effect of human immunodeficiency virus characteristics, smoking, and educational attainment on COPD incidence in PWH. RESULTS: A total of 226 PWH and 1029 population controls were diagnosed with COPD during 63 661 and 562 171 person-years of follow-up. PWH had increased risk of being diagnosed with COPD compared to controls (aHR, 2.02 [95% confidence interval, 1.75-2.33]). Parents and siblings of PWH were also more likely to be diagnosed with COPD compared to controls. CD4+ T-cell counts were not associated with COPD, but unsuppressed viral replication, smoking status, and educational attainment were associated with COPD in PWH. No COPD diagnoses were registered in PWH with high educational attainment and absence of smoking. CONCLUSIONS: PWH have an increased risk of being diagnosed with COPD, as have their parents and siblings. This seems to be driven primarily by smoking and low socioeconomic status.
Contradicts
Integrative bioinformatics frameworks for abdominal aortic aneurysm using GWAS meta-analysis, biological network construction, and structural modeling.
Abstract
Abdominal aortic aneurysm (AAA) is a non-communicable disease (NCD) with high morbidity and mortality, commonly observed worldwide. Understanding its molecular mechanisms and identifying potential therapeutic targets are crucial for disease screening, diagnosis, and treatment. In this study, we conducted a meta-analysis of multiple genome-wide association studies (GWASs) to identify genetic variants associated with AAA and explored the functional implications of these variants in disease pathology. We identified differentially expressed genes (DEGs) based on significant single nucleotide polymorphisms (SNPs) from expression quantitative trait loci (eQTL) and transcriptome-wide association study (TWAS) analyses. Using these DEGs, we constructed an AAA-related protein-protein interaction (PPI) network and prioritized key genes for further analysis. Furthermore, we performed drug repurposing by identifying drug-gene and drug-protein interactions in existing databases and validated potential candidates through molecular docking. Our findings reveal 42 novel disease-associated SNPs and 52 previously unreported disease-related genes. Some residual confounding factors cannot be fully ruled out and may represent a limitation of our study. However, it is worth noting that only a minority of SNPs exhibited heterogeneity. Functional pathways analysis highlighted key processes, including lipid and cholesterol metabolism, tissue remodeling, and acetylcholine activation. We identified 74 D
📖 Linked Papers (30)Export BibTeX ↗
Modulating LRP1 Pathways in Alzheimer's Disease: Mechanistic Insights and Emerging Therapies.
Molecular neurobiology (2026) · PubMed:41772271 ↗
1 figure
Figures
Figures available at source paper (no open-access XML found).
Osteoclast-secreted galectin-3 promotes articular cartilage degeneration in OVX rats via LRP1/beta-catenin axis.
Osteoarthritis Cartilage (2026) · PubMed:40609733 ↗
1 figure
Figures
Figures available at source paper (no open-access XML found).
Astrocytic LRP1 enables mitochondria transfer to neurons and mitigates brain ischemic stroke by suppressing ARF1 lactylation.
Cell metabolism (2024) · PubMed:38906140 ↗
1 figure
Figures
Figures available at source paper (no open-access XML found).
Insulin-like growth factor-1 enhances β-amyloid protein clearance in HMC3 microglia via low-density lipoprotein receptor-related protein 1-mediated pathway.
Experimental cell research (2026) · PubMed:41621577 ↗
No figures
Lysosomal trafficking markers covering PSAP, PGRN, SORT1 and LRP1 in body liquids and cerebral tissue as auxiliary indicative tool of traumatic brain injury.
Forensic science international (2026) · PubMed:41579784 ↗
No figures
Schwann cell Lrp1 deletion drives trigeminal neuron sensitization and orofacial pain by modulating mitochondrial function and TRPV1/TRPA1 activity.
The journal of headache and pain (2025) · PubMed:41430102 ↗
No figures
Ganglioside sialylation modulates tau internalization and pathology spread.
Molecular psychiatry (2025) · PubMed:41398374 ↗
No figures
Inhibition of tau neuronal internalization using anti-tau single domain antibodies.
Nature communications (2025) · PubMed:40175345 ↗
No figures
Microglia internalize tau monomers and fibrils using distinct receptors but similar mechanisms.
Alzheimer's & dementia : the journal of the Alzheimer's Association (2025) · PubMed:39713861 ↗
No figures
📙 Related Wiki Pages (15)
NTS — NeurotensingeneTERC GenegeneTau Propagation MechanismsmechanismLRP1 (Low-Density Lipoprotein Receptor-RproteinLRP1 GenegeneAstrocyte-Derived Exosomal mRNA ReferencbiomarkerEEG Biomarkers for Alzheimer's DiseasebiomarkerEye-Tracking Digital Markers in AlzheimebiomarkerDigital Biomarkers for Alzheimer's DiseabiomarkerCombination Biomarker Panels for AlzheimbiomarkerASL Perfusion Biomarkers for Alzheimer'sbiomarkerAlzheimer's Disease BiomarkersbiomarkerBlood p-Tau217 as a Clock for Alzheimer'mechanismBlood p-Tau181 and p-Tau217 Elevated in biomarkerDried Blood Spot Biomarker Test for Alzhbiomarker
🏥 Translation
🧬 3D Protein Structure — LRP1
🧠 GTEx v10 Brain ExpressionJSON
Median TPM across 13 brain regions for LRP1 from GTEx v10.
💉 Clinical Trials (11)Relevance: 100%
0
Active
Active
0
Completed
Completed
1,858
Total Enrolled
Total Enrolled
PHASE1
Highest Phase
Highest Phase
COMPLETED·NCT02463084 · Wake Forest University Health Sciences
60 enrolled · 2013-03 · → 2016-06
This study compares the effects of a one-month diet high in saturated fat (SF), glycemic index (GI), and salt (Na+) to a diet low in these nutritional parameters on memory and other cognitive function
Prediabetic State Insulin Resistance Middle Age
Low Diet High Diet
TERMINATED·NCT01497665 · Angiochem Inc
16 enrolled · 2011-11 · → 2013-01
The purpose of this study is to assess the efficacy, safety, and tolerability of GRN1005 in patients with brain metastases from non-small cell lung cancer (NSCLC).
Non-small Cell Lung Cancer (NSCLC) With Brain Metastases
GRN1005
COMPLETED·NCT02048059 · Angiochem Inc
72 enrolled · 2014-04 · → 2016-03
This is a Phase 2 study to see if an investigational drug, ANG1005, can shrink tumor cells in breast cancer patients with recurrent brain metastases.
Breast Cancer Brain Metastases
ANG1005
UNKNOWN·NCT05301153 · Assiut University
82 enrolled · 2022-07-01 · → 2023-12-01
Myasthenia gravis is a B-cell-mediated autoimmune disorders causing muscle weakness due to defective synaptic transmission at the neuromuscular junction caused by autoantibodies to acetylcholine recep
Myasthenia Gravis
real time PCR , ELISA
ACTIVE_NOT_RECRUITING·NCT04688788 · Rigshospitalet, Denmark
600 enrolled · 2021-04-28 · → 2026-05-05
The DanNORMS study is a phase 3, non-inferiority clinical trial examining whether treatment of active multiple sclerosis with rituximab is non-inferior to ocrelizumab regarding efficacy and safety.
Relapsing Remitting Multiple Sclerosis Secondary Progressive Multiple Sclerosis Primary Progressive Multiple Sclerosis
Rituximab Ocrelizumab Fexofenadine
COMPLETED·NCT02786602 · CHU de Reims
345 enrolled · 2016-05 · → 2016-11
Colorectal cancer (CRC) is a major public health problem in France and worldwide. CRC is the third most common cancer in incidence and mortality in France. The vast majority of these cancers are adeno
Colon Cancer
pyrosequencing
COMPLETED·NCT01661673 · FORUM Pharmaceuticals Inc
52 enrolled · 2012-11 · → 2013-10
This study is being conducted to determine the safety, tolerability, pharmacokinetics, and effects of EVP-0962 on cerebral spinal fluid Amyloid concentrations in healthy subjects and in subjects with
Mild Cognitive Impairment Alzheimer's Disease
EVP-0962 Placebo
Comprehensive Home-based Dementia Care Coordination for Medicare-Medicaid Dual Eligibles in MarylandNA
COMPLETED·NCT02395731 · Johns Hopkins University
342 enrolled · 2015-03 · → 2017-11-30
This Center for Medicare and Medicaid funded health care innovation award will implement the MIND at Home dementia care coordination program (called MIND at Home-Plus) through two community-based serv
Dementia Caregiver Burden
MIND at Home-Plus Intervention
COMPLETED·NCT01055561 · Chengdu University of Traditional Chinese Medicine
30 enrolled · 2010-01 · → 2011-02
The purpose of the study is to evaluate the safety and tolerability of acupuncture for patients with BPSD \& healthy volunteers.
Alzheimer's Disease Dementia
Acupuncture
UNKNOWN·NCT02987842 · Beersheva Mental Health Center
30 enrolled · 2016-12 · → 2017-12
This study protocol proposes an EEG based neurofeedback (EEG-NFB) technique to upregulate the posterior cingulate cortex (PCC) in patients suffering from mild cognitive impairment (MCI) and early Alzh
Mild Cognitive Impairment Alzheimer Disease
TruScan Neurofeedback
COMPLETED·NCT00096473 · Eisai Inc.
229 enrolled · 2001-01 · → 2005-06
Donepezil hydrochloride (Aricept) has been approved to treat symptoms associated with mild to moderate Alzheimer's disease (AD). Aricept has been shown to improve the memory and thinking abilities, ac
Alzheimer's Disease Dementia
Donepezil hydrochloride
No curated ClinVar variants loaded for this hypothesis.
Run scripts/backfill_clinvar_variants.py to fetch P/LP/VUS variants.
No DepMap CRISPR Chronos data found for LRP1.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
💰 Estimated Development
Cost
$1
Timeline
2.3 years
🏆 Tournament
🏆 Arenas / Elo
No arena matches recorded yet. Browse Arenas →
📊 Market Indicators
7d Trend
↔
Stable
7d Momentum
▼ 0.7%
Volatility
Low
0.0095
Events (7d)
2
Price History
▲59.3%💾 Resource Usage
LLM Tokens
537,676
$1.6130
Total Cost
$1.6130
🔮 Predictions
🔎 Predictions vs Observations1 predictions · 0 with recorded observations
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| Test prediction | Test outcome | — no observation — | pending | 0.70 |
🔮 Falsifiable Predictions (1)
pendingconf 70%
Test prediction
Predicted outcome: Test outcome
Falsification: If test fails
📖 References (9)
- Regulation of tau internalization, degradation, and seeding by LRP1 reveals multiple pathways for tau catabolism.["Cooper J" et al.. The Journal of biological chemistry (2021)
- World Cancer Research Fund’s campaign helps people take control of cancer riskKate Allen. BMJ (Clinical research ed.) (2018)
- LRP1 is a neuronal receptor for α-synuclein uptake and spread.["Chen K" et al.. Molecular neurodegeneration (2022)
- Distinct cellular dynamics associated with response to CAR-T therapy for refractory B cell lymphoma.["Haradhvala N" et al.. Nature medicine (2022)
- Editorial for “Corrected <scp>MRI</scp> Pulmonary Transit Time for Identification of Combined Pre and PostCapillary Pulmonary Hypertension in Patients With Left Heart Disease”Ricci Fabrizio; Khanji Mohammed Y; Garg Pankaj. Journal of Magnetic Resonance Imaging (2023)
- Inhibition of tau neuronal internalization using anti-tau single domain antibodies.["Danis C" et al.. Nature communications (2025)
- Modulating LRP1 Pathways in Alzheimer's Disease: Mechanistic Insights and Emerging Therapies.Mushtaq T et al.. Molecular neurobiology (2026)
- Mitochondrial calcium uniporter knockdown in hippocampal neurons effectively attenuates synaptic plasticity impairment and pathology in APP/PS1/tau model of Alzheimer's disease.Wu L et al.. Experimental neurology (2026)
- Insulin-like growth factor-1 enhances β-amyloid protein clearance in HMC3 microglia via low-density lipoprotein receptor-related protein 1-mediated pathway.Guo H et al.. Experimental cell research (2026)
Related Entities
▸Metadata
| status | proposed |
| _schema_version | 1 |
| hypothesis_type | None |
📊 Evidence Profile
Foundational
Evidence Balance
+0%
Certainty
100%
Debates
0
Incoming
2809
Outgoing
1126
0 supporting
0 contradicting
0 neutral
Public annotations (0)Annotate on Hypothes.is →
No public annotations yet.