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Abstract

Golgi fragmentation occurs in neurons of patients with Alzheimerâ��s disease (AD), but the underlying molecular mechanism causing the defects and the subsequent effects on disease development remain unknown. In this study, we examined the Golgi structure in APPswe/PS1��E9 transgenic mouse and tissue culture models. Our results suggest that A�² accumulation leads to Golgi fragmentation by activating cdk5, which in turn phosphorylates GRASP65 and perhaps other key proteins critical for maintaining Golgi morphology. Significantly, rescue of Golgi structural defects by inhibiting cdk5 or by expressing non-phosphorylatable mutants of GRASP65 reduces A�² secretion by elevating non-amyloidogenic APP cleavage. These results reveal Golgi fragmentation as an important mechanism through which A�² may exert its toxic effects. A major potential unrecognized source of A�² toxicity may be that it compromises Golgi integrity and perturbs the proper trafficking and processing of many proteins essential for neuronal function. We hypothesize that in AD, A�² accumulation promotes Golgi defects, which in turn accelerate APP trafficking and A�² production; this deleterious feedback circuit would impair the integrity of the secretory pathway and thereby compromise neuronal cell function. Our study provides a molecular mechanism for Golgi fragmentation and its effects on APP trafficking and processing in AD, suggesting Golgi as a potential drug target for AD treatment.

Biography

Email: yzwang@umich.edu