| First Author | Mosser S | Year | 2015 |
| Journal | Hum Mol Genet | Volume | 24 |
| Issue | 2 | Pages | 371-82 |
| PubMed ID | 25180020 | Mgi Jnum | J:217062 |
| Mgi Id | MGI:5613026 | Doi | 10.1093/hmg/ddu449 |
| Citation | Mosser S, et al. (2015) The adipocyte differentiation protein APMAP is an endogenous suppressor of Abeta production in the brain. Hum Mol Genet 24(2):371-82 |
| abstractText | The deposition of amyloid-beta (Abeta) aggregates in the brain is a major pathological hallmark of Alzheimer's disease (AD). Abeta is generated from the cleavage of C-terminal fragments of the amyloid precursor protein (APP-CTFs) by gamma-secretase, an intramembrane-cleaving protease with multiple substrates, including the Notch receptors. Endogenous modulation of gamma-secretase is pointed to be implicated in the sporadic, age-dependent form of AD. Moreover, specifically modulating Abeta production has become a priority for the safe treatment of AD because the inhibition of gamma-secretase results in adverse effects that are related to impaired Notch cleavage. Here, we report the identification of the adipocyte differentiation protein APMAP as a novel endogenous suppressor of Abeta generation. We found that APMAP interacts physically with gamma-secretase and its substrate APP. In cells, the partial depletion of APMAP drastically increased the levels of APP-CTFs, as well as uniquely affecting their stability, with the consequence being increased secretion of Abeta. In wild-type and APP/ presenilin 1 transgenic mice, partial adeno-associated virus-mediated APMAP knockdown in the hippocampus increased Abeta production by approximately 20 and approximately 55%, respectively. Together, our data demonstrate that APMAP is a negative regulator of Abeta production through its interaction with APP and gamma-secretase. All observed APMAP phenotypes can be explained by an impaired degradation of APP-CTFs, likely caused by an altered substrate transport capacity to the lysosomal/autophagic system. |
