Aβ-induced Golgi fragmentation in Alzheimer’s disease enhances Aβ production

Significance In Alzheimer’s disease (AD), formation of the Aβ aggregates occurs by the cleavage of the amyloid precursor protein (APP) during its trafficking inside the nerve cells. The Golgi apparatus plays a critical role in APP trafficking; fragmentation of the normally highly ordered Golgi structure occurs in nerve cells of AD patients. Here we report that Aβ accumulation triggers Golgi fragmentation by activating cyclin-dependent kinase-5 (cdk5), which phosphorylates Golgi structural proteins such as GRASP65. Rescue of Golgi structure by inhibiting cdk5 or by expressing nonphosphorylatable GRASP65 mutants reduced Aβ secretion. Our study provides a molecular mechanism for Golgi fragmentation and its effects on APP trafficking and processing, suggesting Golgi as a potential drug target for AD treatment. Golgi fragmentation occurs in neurons of patients with Alzheimer’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 show that accumulation of amyloid beta peptides (Aβ) leads to Golgi fragmentation. Further biochemistry and cell biology studies revealed that Golgi fragmentation in AD is caused by phosphorylation of Golgi structural proteins, such as GRASP65, which is induced by Aβ-triggered cyclin-dependent kinase-5 activation. Significantly, both inhibition of cyclin-dependent kinase-5 and expression of nonphosphorylatable GRASP65 mutants rescued the Golgi structure and reduced Aβ secretion by elevating α-cleavage of the amyloid precursor protein. Our study demonstrates a molecular mechanism for Golgi fragmentation and its effects on amyloid precursor protein trafficking and processing in AD, suggesting Golgi as a potential drug target for AD treatment.

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