title: Extracellular association of APP and tau fibrils induces intracellular aggregate formation of tau.
abstract: Alzheimer's disease (AD) is characterized by extracellular amyloid β (Aβ) deposition and intracellular tau aggregation. Many studies have indicated some association between these processes, but it remains unknown how the two pathologies are linked. In this study, we investigated whether expression of amyloid precursor protein (APP) influences extracellular seed-dependent intracellular tau accumulation in cultured cells. Treatment of tau-expressing SH-SY5Y cells with Aβ fibrils did not induce intracellular tau aggregation. On the other hand, in cells expressing both tau and APP, treatment with tau fibrils or Sarkosyl-insoluble tau from AD brains induced intracellular tau aggregation. The seed-dependent intracellular tau aggregation was not induced by expression of APP lacking the extracellular domain. The amount of phosphorylated tau aggregates in cultured cells was dose dependently elevated in response to increased levels of APP on the cell membrane. Our results indicate that the extracellular region of APP is involved in uptake of tau fibrils into cells, raising the possibility that APP, but not Aβ, influences cell-to-cell spreading of tau pathologies in AD by serving as a receptor of abnormal tau aggregates.
authors: Department of Dementia and Higher Brain Function, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo, 156-8506, Japan.
authors: Muneaki
authors: M
authors: Takahashi
authors: Haruka
authors: H
authors: Miyata
authors: Fuyuki
authors: F
authors: Kametani
authors: Takashi
authors: T
authors: Nonaka
authors: Haruhiko
authors: H
authors: Akiyama
authors: Shin-ichi
authors: S
authors: Hisanaga
authors: Masato
authors: M
authors: Hasegawa
mesh_terms: D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000378:metabolism* / Q000648:ultrastructure; D004305:Dose-Response Relationship, Drug; D045604:Extracellular Fluid / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D018613:Microscopy, Confocal; D016253:Microscopy, Immunoelectron; D009154:Mutation / Q000235:genetics; D009447:Neuroblastoma / Q000473:pathology; D014162:Transfection; D016875:tau Proteins / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D016875:tau Proteins