ArticleeLife2021
Amphiphysin I cleavage by asparagine endopeptidase leads to tau hyperphosphorylation and synaptic dysfunction.
Article in eLife, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 18 citations in OpenAlex.
- BIN1 Interacts with Tau Fragments to Inhibit TrkB Signaling Endosome Recycling in a Mouse Model of Alzheimer's Disease.Neuroscience bulletin · 2026Article
- Pharmacologic reversal of advanced Alzheimer's disease in mice and identification of potential therapeutic nodes in human brain.Cell reports. Medicine · 2026Article
- CDK5-mediated hyperphosphorylation of Tau217 impairs neuronal synaptic structure and exacerbates cognitive impairment in Alzheimer's disease.Translational psychiatry · 2025Article
- Systems genetics reveals the influence of expression QTLs in mouse embryonic stem cells on transcriptional variation later in differentiated neural progenitor cells.G3 (Bethesda, Md.) · 2025Article
- Cross cell-type systems genetics reveals the influence of eQTL at multiple points in the developmental trajectory of mouse neural progenitor cells.bioRxiv : the preprint server for biology · 2025Article
- GDF1 ameliorates cognitive impairment induced by hearing loss.Nature aging · 2024Article
- Bridging integrator 1 fragment accelerates tau aggregation and propagation by enhancing clathrin-mediated endocytosis in mice.PLoS biology · 2024Article
- Asparagine endopeptidase protects podocytes in adriamycin-induced nephropathy by regulating actin dynamics through cleaving transgelin.Molecular therapy : the journal of the American Society of Gene Therapy · 2023Article
- Soluble TREM2 ameliorates tau phosphorylation and cognitive deficits through activating transgelin-2 in Alzheimer's disease.Nature communications · 2023Article
- The Mammalian Cysteine Protease Legumain in Health and Disease.International journal of molecular sciences · 2022Review
- Ubiquitin ligase activity inhibits Cdk5 to control axon termination.PLoS genetics · 2022Article
- Silica Nanoparticles Promote α-Synuclein Aggregation and Parkinson's Disease Pathology.Frontiers in neuroscience · 2021Article
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Authors and funding
16 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Neurofibrillary tangles composed of hyperphosphorylated tau and synaptic dysfunction are characteristics of Alzheimer's disease (AD). However, the underlying molecular mechanisms remain poorly understood. Here, we identified Amphiphysin I mediates both tau phosphorylation and synaptic dysfunction in AD. Amphiphysin I is cleaved by a cysteine proteinase asparagine endopeptidase (AEP) at N278 in the brains of AD patients. The amount of AEP-generated N-terminal fragment of Amphiphysin I (1-278) is increased with aging. Amphiphysin I (1-278) inhibits clathrin-mediated endocytosis and induces synaptic dysfunction. Furthermore, Amphiphysin I (1-278) binds p35 and promotes its transition to p25, thus activates CDK5 and enhances tau hyperphosphorylation. Overexpression of Amphiphysin I (1-278) in the hippocampus of Tau P301S mice induces synaptic dysfunction, tau hyperphosphorylation, and cognitive deficits. However, overexpression of the N278A mutant Amphiphysin I, which resists the AEP-mediated cleavage, alleviates the pathological and behavioral defects. These findings suggest a mechanism of tau hyperphosphorylation and synaptic dysfunction in AD.
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