부산대학교 도서관

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 (A[beta]) 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 A[beta] production and deposition into senile plaques. To investigate at the molecular level the neurobiological functions of APMAP (memory and A[beta] formation) and a possible link with the pathological hallmarks of AD (memory impairment and A[beta] 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 A[beta] production, while clusterin, calnexin, arginase-1, PTGFRN and the cation-independent mannose-6-phosphate receptor (CI-M6PR/IGF2R) positively regulated APP and A[beta] 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 A[beta] generation. Importantly, we have also demonstrated increased alternative splicing of APMAP and lowered levels of the A[beta] controllers HSPA1A and CD-M6PR in human brains from neuropathologically verified AD cases. Keywords: Neurodegeneration, Alzheimer's disease, APMAP-KO, Learning and memory, APMAP interactome, A[beta] production, Alternative splicing
Author(s): Hermeto Gerber[sup.1,2,3] , Sebastien Mosser[sup.1,2] , Benjamin Boury-Jamot[sup.4] , Michael Stumpe[sup.3] , Alessandra Piersigilli[sup.5,6] , Christine Goepfert[sup.5,6] , Joern Dengjel[sup.3] , Urs Albrecht[sup.3] , Fulvio Magara[sup.4] and Patrick C. [...]