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P2‐151: PICALM regulates Aβ42 production by modulation of gamma‐secretase trafficking
Author(s) -
Tomita Taisuke,
Morohashi Yuichi,
Kanatsu Kunihiko,
Iwatsubo Takeshi
Publication year - 2012
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2012.05.857
Subject(s) - endocytic cycle , endocytosis , clathrin , microbiology and biotechnology , biology , cell , biochemistry
Background: Alzheimer disease (AD) is the most common type of dementia worldwide. Several lines of evidence suggest that aberrant production, clearance and aggregation of amyloid-beta peptide (Ab) in human brain are linked to the etiology of AD. Recently, genome-wide association studies in late-onset AD patients have reported evidence that variation in phosphatidylinositol binding clathrin assembly protein (PICALM) gene confer genetic risk for AD. Methods: To investigate the role of PICALM in Ab generation, we analyzed the effects of knockdown or overexpression of PICALM in cultured cells on the processing of amyloid precursor protein (APP). We also monitored the trafficking of the gamma-secretase by monoclonal antibody A5226A, which recognizes the extracellular domain of mature Nicastrin on the cell surface (Hayashi et al., Oncogene 2011). Results: Depletion of PICALM caused a decrease in the production ratio of Ab42, the most aggregable Ab species. Moreover, PICALM RNAi altered the endocytic rate of gamma-secretase, while the endocytosis of transferrin, one of the typical cargo proteins for clathrin-mediated endocytosis, was not affected. In contrast, total Ab levels as well as Ab42 ratio were increased by the overexpression of PICALM. Conclusions: These results suggest PICALMmodulates gamma-secretase activity by regulating its clathrin-mediated endocytosis. Alteration in endocytic rate of gamma-secretase by PICALM RNAi/overexpression may change its steady-state subcellular localization, leading to alteration in both the total Ab generation and the Ab42 ratio.