| First Author | Gerber H | Year | 2019 |
| Journal | Acta Neuropathol Commun | Volume | 7 |
| Issue | 1 | Pages | 13 |
| PubMed ID | 30704515 | Mgi Jnum | J:273177 |
| Mgi Id | MGI:6283960 | Doi | 10.1186/s40478-019-0660-3 |
| Citation | Gerber H, et al. (2019) The APMAP interactome reveals new modulators of APP processing and beta-amyloid production that are altered in Alzheimer's disease. Acta Neuropathol Commun 7(1):13 |
| abstractText | The adipocyte plasma membrane-associated protein APMAP is expressed in the brain where it associates with gamma-secretase, a protease responsible for the generation of the amyloid-beta peptides (Abeta) implicated in the pathogenesis of Alzheimer's disease (AD). In this study, behavioral investigations revealed spatial learning and memory deficiencies in our newly generated mouse line lacking the protein APMAP. In a mouse model of AD, the constitutive deletion of APMAP worsened the spatial memory phenotype and led to increased Abeta production and deposition into senile plaques. To investigate at the molecular level the neurobiological functions of APMAP (memory and Abeta formation) and a possible link with the pathological hallmarks of AD (memory impairment and Abeta pathology), we next developed a procedure for the high-grade purification of cellular APMAP protein complexes. The biochemical characterization of these complexes revealed a series of new APMAP interactomers. Among these, the heat shock protein HSPA1A and the cation-dependent mannose-6-phosphate receptor (CD-M6PR) negatively regulated APP processing and Abeta production, while clusterin, calnexin, arginase-1, PTGFRN and the cation-independent mannose-6-phosphate receptor (CI-M6PR/IGF2R) positively regulated APP and Abeta production. Several of the newly identified APMAP interactomers contribute to the autophagy-lysosome system, further supporting an emergent agreement that this pathway can modulate APP metabolism and Abeta generation. Importantly, we have also demonstrated increased alternative splicing of APMAP and lowered levels of the Abeta controllers HSPA1A and CD-M6PR in human brains from neuropathologically verified AD cases. |
