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Late endocytic dysfunction as a putative cause of amyloid fibril formation in Alzheimer’s disease
Author(s) -
Yuyama Kohei,
Yanagisawa Katsuhiko
Publication year - 2009
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2009.06046.x
Subject(s) - endocytic cycle , endosome , fibril , amyloid (mycology) , biochemistry of alzheimer's disease , microbiology and biotechnology , p3 peptide , chemistry , endocytosis , amyloid precursor protein , senile plaques , alzheimer's disease , biology , biochemistry , cell , pathology , medicine , inorganic chemistry , intracellular , disease
The assembly of amyloid β‐protein to amyloid fibrils is a critical event in Alzheimer’s disease. Evidence exists that endocytic pathway abnormalities, including the enlargement of early endosomes, precede the extraneuronal amyloid fibril deposition in the brain. We determined whether endocytic dysfunction potently promotes the assembly of amyloid β‐protein on the surface of cultured cells. Blocking the early endocytic pathway by clathrin suppression, inactivation of small GTPases, removal of membrane cholesterol, and Rab5 knockdown did not result in amyloid fibril formation on the cell surface from exogenously added soluble amyloid β‐protein. In contrast, blocking the late endocytic pathway by Rab7 suppression markedly induced the amyloid fibril formation in addition to the enlargement of early endosomes. Notably, a monoclonal antibody specific to GM1‐ganglioside‐bound amyloid β‐protein, an endogenous seed for Alzheimer amyloid, completely blocks the amyloid fibril formation. Our results suggest that late but not early endocytic dysfunction contributes to the amyloid fibril formation by facilitating the generation of amyloid seed in the Alzheimer’s brain.