| First Author | Kanatsu K | Year | 2016 |
| Journal | Hum Mol Genet | Volume | 25 |
| Issue | 18 | Pages | 3988-3997 |
| PubMed ID | 27466196 | Mgi Jnum | J:238571 |
| Mgi Id | MGI:5823105 | Doi | 10.1093/hmg/ddw239 |
| Citation | Kanatsu K, et al. (2016) Partial loss of CALM function reduces Abeta42 production and amyloid deposition in vivo. Hum Mol Genet 25(18):3988-3997 |
| abstractText | Aberrant production, clearance and deposition of amyloid-beta protein (Abeta) in the human brain have been implicated in the aetiology of Alzheimer disease (AD). gamma-Secretase is the enzyme responsible for generating various Abeta species, such as Abeta40 and toxic Abeta42. 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 Abeta42, through the regulation of the clathrin-mediated endocytosis of gamma-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 Abeta42 production ratio. Moreover, reduction of CALM decreases Abeta deposition as well as brain levels of insoluble Abeta42 in vivo These results suggest that CALM expression modifies AD risk by regulating Abeta pathology. |
