ArticlePLoS biology2024
Bridging integrator 1 fragment accelerates tau aggregation and propagation by enhancing clathrin-mediated endocytosis in mice.
Article in PLoS biology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 13 citations in OpenAlex.
- Lysosomal dysfunction in neurodegenerative disease.Nature reviews. Neurology · 2026Review
- Traumatic Brain Injury and the Road to Alzheimer's Disease.Biomedicines · 2026Review
- Bridging autophagy and endolysosomal dysfunction: Role of bridging integrator 1 in Alzheimer's disease.Neural regeneration research · 2026Article
- Shared genetic architecture between Alzheimer's disease and brain morphology.Alzheimer's research & therapy · 2026Article
- BIN1 Interacts with Tau Fragments to Inhibit TrkB Signaling Endosome Recycling in a Mouse Model of Alzheimer's Disease.Neuroscience bulletin · 2026Article
- Emerging pathological mechanisms of Alzheimer's disease pathogenesis: from neuroimmune interactions to intercellular communication.Frontiers in aging neuroscience · 2026Review
- From seeds to symptoms: the molecular landscape of tau seeding in Alzheimer's disease.Frontiers in neuroscience · 2026Review
- Proteomic analysis links truncated tau to lysosome motility, autophagy, and endo-lysosomal dysfunction.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Article
- A Single-Chain Variable Fragment Antibody Alleviates Inflammation and Apoptosis of Neurons by Inhibiting Tau Aggregation.Biomolecules · 2025Article
- Clathrin mediated endocytosis in Alzheimer's disease: cell type specific involvement in amyloid beta pathology.Frontiers in aging neuroscience · 2024Review
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Authors and funding
12 authors at 2 institutions in 1 country.
Funding
Abstract
The bridging integrator 1 (BIN1) gene is an important risk locus for late-onset Alzheimer's disease (AD). BIN1 protein has been reported to mediate tau pathology, but the underlying molecular mechanisms remain elusive. Here, we show that neuronal BIN1 is cleaved by the cysteine protease legumain at residues N277 and N288. The legumain-generated BIN1 (1-277) fragment is detected in brain tissues from AD patients and tau P301S transgenic mice. This fragment interacts with tau and accelerates its aggregation. Furthermore, the BIN1 (1-277) fragment promotes the propagation of tau aggregates by enhancing clathrin-mediated endocytosis (CME). Overexpression of the BIN1 (1-277) fragment in tau P301S mice facilitates the propagation of tau pathology, inducing cognitive deficits, while overexpression of mutant BIN1 that blocks its cleavage by legumain halts tau propagation. Furthermore, blocking the cleavage of endogenous BIN1 using the CRISPR/Cas9 gene-editing tool ameliorates tau pathology and behavioral deficits. Our results demonstrate that the legumain-mediated cleavage of BIN1 plays a key role in the progression of tau pathology. Inhibition of legumain-mediated BIN1 cleavage may be a promising therapeutic strategy for treating AD.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.