Journal
HUMAN MOLECULAR GENETICS
Volume 25, Issue 18, Pages 3988-3997Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddw239
Keywords
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Funding
- Japan Society for the Promotion of Science (JSPS) [15H02492]
- Ministry of Education, Culture, Sports, Science and Technology [22110003, 26111705]
- Japan Agency for Medical Research and Development [14028022, 15653129]
- Daiichi Sankyo Foundation of Life Science
- Ono Medical Research Foundation
- NAGASE Science Technology Foundation
- Grants-in-Aid for Scientific Research [14028022, 26111705, 22110003, 15H02492] Funding Source: KAKEN
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Aberrant production, clearance and deposition of amyloid-beta protein (A beta) in the human brain have been implicated in the aetiology of Alzheimer disease (AD). gamma-Secretase is the enzyme responsible for generating various Ab species, such as A beta 40 and toxic A beta 42. Recently, genome-wide association studies in late-onset AD patients have identified the endocytosis-related phosphatidylinositol-binding clathrin assembly protein (PICALM) gene as a genetic risk factor for AD. We previously found that the loss of expression of CALM protein encoded by PICALM affects the ratio of production of A beta 42, through the regulation of the clathrin-mediated endocytosis of c-secretase. Here, we show that the binding capacity of the assembly protein 180 N-terminal homology (ANTH) domain of CALM to phosphatidylinositol-4,5-biphosphate, as well as to nicastrin, is critical to the modulation of the internalization of gamma-secretase and to the A beta 42 production ratio. Moreover, reduction of CALM decreases Ab deposition as well as brain levels of insoluble A beta 42 in vivo. These results suggest that CALM expression modifies AD risk by regulating Ab pathology.
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