ArticleThe Journal of biological chemistry2021
Alzheimer's disease BIN1 coding variants increase intracellular Aβ levels by interfering with BACE1 recycling.
Article in The Journal of biological chemistry, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 32 citations in OpenAlex.
- Bridging autophagy and endolysosomal dysfunction: Role of bridging integrator 1 in Alzheimer's disease.Neural regeneration research · 2026Article
- Interactome mapping in human excitatory neurons reveals novel risk genes and pathways in Alzheimer's disease.bioRxiv : the preprint server for biology · 2026Article
- BIN1 Interacts with Tau Fragments to Inhibit TrkB Signaling Endosome Recycling in a Mouse Model of Alzheimer's Disease.Neuroscience bulletin · 2026Article
- Article
- Alzheimer's genetic risk factor Bin1 controls synapse vesicle exo-endocytosis in inhibitory synapses.Cell reports · 2025Article
- Recent Advances and Future Directions in Alzheimer's Disease Genetic Research.International journal of molecular sciences · 2025Review
- Bend it like BIN1: how a membrane-curving adaptor protein shapes cardiac physiology.American journal of physiology. Heart and circulatory physiology · 2025Review
- Ancestrally diverse genome-wide association analysis highlights ancestry-specific differences in genetic regulation of plasma protein levels.medRxiv : the preprint server for health sciences · 2024Article
- Native-state proteomics of Parvalbumin interneurons identifies unique molecular signatures and vulnerabilities to early Alzheimer's pathology.Nature communications · 2024Article
- BIN1Alzheimer's & dementia : the journal of the Alzheimer's Association · 2024Article
- Alzheimer's Disease: Models and Molecular Mechanisms Informing Disease and Treatments.Bioengineering (Basel, Switzerland) · 2024Review
- BIN1 in the Pursuit of Ousting the Alzheimer's Reign: Impact on Amyloid and Tau Neuropathology.Neurotoxicity research · 2023Review
- Integrative single-nucleus multi-omics analysis prioritizes candidate cis and trans regulatory networks and their target genes in Alzheimer's disease brains.Cell & bioscience · 2023Article
- A Systematic Compilation of Human SH3 Domains: A Versatile Superfamily in Cellular Signaling.Cells · 2023Review
- Alzheimer's Disease: An Updated Overview of Its Genetics.International journal of molecular sciences · 2023Review
- Gut-brain connections in neurodegenerative disease: immunotherapeutic targeting of Bin1 in inflammatory bowel disease and Alzheimer's disease.Frontiers in pharmacology · 2023Review
- Review
- Endosomal trafficking and related genetic underpinnings as a hub in Alzheimer's disease.Journal of cellular physiology · 2022Review
- Lower expression ofJournal of Alzheimer's disease reportsArticle
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Genetic studies have identified BIN1 as the second most important risk locus associated with late-onset Alzheimer's disease (LOAD). However, it is unclear how mutation of this locus mechanistically promotes Alzheimer's disease (AD) pathology. Here we show the consequences of two coding variants in BIN1 (rs754834233 and rs138047593), both in terms of intracellular beta-amyloid (iAbeta) accumulation and early endosome enlargement, two interrelated early cytopathological AD phenotypes, supporting their association with LOAD risk. We previously found that Bin1 deficiency potentiates iAbeta production by enabling BACE1 cleavage of the amyloid precursor protein in enlarged early endosomes due to decreased BACE1 recycling. Here, we discovered that the expression of the two LOAD mutant forms of Bin1 does not rescue the iAbeta accumulation and early endosome enlargement induced by Bin1 knockdown and recovered by wild-type Bin1. Moreover, the overexpression of Bin1 mutants, but not wild-type Bin1, increased the iAbeta42 fragment by reducing the recycling of BACE1, which accumulated in early endosomes, recapitulating the phenotype of Bin1 knockdown. We showed that the mutations in Bin1 reduced its interaction with BACE1. The endocytic recycling of transferrin was similarly affected, indicating that Bin1 is a general regulator of endocytic recycling. These data demonstrate that the LOAD-coding variants in Bin1 lead to a loss of function in endocytic recycling, which may be an early causal mechanism of LOAD.
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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 Socratic graph.