{"entity": "publication", "iuid": "d89c90552d974d6ea6979a3c189833fe", "timestamp": "2026-06-12T23:26:08.445Z", "links": {"self": {"href": "https://publications.scilifelab.se/publication/d89c90552d974d6ea6979a3c189833fe.json"}, "display": {"href": "https://publications.scilifelab.se/publication/d89c90552d974d6ea6979a3c189833fe"}}, "title": "Intraneuronal A\u03b2 accumulation causes tau hyperphosphorylation via endolysosomal leakage.", "authors": [{"family": "Gao", "given": "Yang", "initials": "Y", "orcid": "0000-0002-7733-5365", "researcher": {"href": "https://publications.scilifelab.se/researcher/b3c1d375765a41e0b0a7d2c0af9cb4ff.json"}}, {"family": "Wang", "given": "Lisha", "initials": "L"}, {"family": "Doeswijk", "given": "Tosca", "initials": "T"}, {"family": "Winblad", "given": "Bengt", "initials": "B"}, {"family": "Schedin-Weiss", "given": "Sophia", "initials": "S"}, {"family": "Tjernberg", "given": "Lars O", "initials": "LO", "orcid": "0000-0001-6889-4950", "researcher": {"href": "https://publications.scilifelab.se/researcher/35d7bd25361f4e08a7223926311b399a.json"}}], "type": "journal article", "published": "2025-03-00", "journal": {"title": "Alzheimers Dement", "issn": "1552-5279", "volume": "21", "issue": "3", "pages": "e70091", "issn-l": null}, "abstract": "Alzheimer's disease (AD) is characterized by amyloid beta (A\u03b2) peptide plaques and intracellular neurofibrillary tangles formed by hyperphosphorylated tau. Many attempts have been made to clarify the link between A\u03b2 and tau in the pathogenesis, but conclusive data describing a pathway for this connection are still lacking.\n\nWe developed a neuronal model of A\u03b2-induced toxicity and studied downstream effects of intraneuronal A\u03b242 accumulation on tau hyperphosphorylation using confocal microscopy and live cell imaging.\n\nA\u03b242 added to the medium was endocytosed into neurons, inducing the formation of endolysosomal protofibrils and endolysosomal leakage, which in turn promoted tau hyperphosphorylation. Asparaginyl endopeptidase (AEP) was released from the disrupted lysosomes, and inhibition of this peptidase activity reduced tau hyperphosphorylation.\n\nThe data suggest a mechanism of AD in which A\u03b242 accumulates and aggregates gradually in neurons over time, leading to endolysosomal leakage and release of AEP, which subsequently triggers tau hyperphosphorylation.\n\nA\u03b242 endocytosis leads to its endolysosomal accumulation in neurons over time. A\u03b242 polymerizes into protofibrils and causes endolysosomal leakage. Tau hyperphosphorylation is induced by endolysosomal asparagine endopeptidase leakage. Tau hyperphosphorylation is inhibited by an asparagine endopeptidase inhibitor.", "doi": "10.1002/alz.70091", "pmid": "40145397", "labels": {"Integrated Microscopy Technologies Stockholm": "Service"}, "xrefs": [{"db": "pmc", "key": "PMC11947758"}], "notes": [], "created": "2026-06-11T12:35:12.376Z", "modified": "2026-06-11T12:35:30.496Z"}