title: Aβ-induced Golgi fragmentation in Alzheimer's disease enhances Aβ production.
abstract: 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/PS1E9 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.
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI 48109.
authors.forename: Gunjan
authors.initials: G
authors.lastname: Joshi
authors.forename: Youjian
authors.initials: Y
authors.lastname: Chi
authors.forename: Zheping
authors.initials: Z
authors.lastname: Huang
authors.forename: Yanzhuang
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000096:biosynthesis* / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D002352:Carrier Proteins / Q000378:metabolism; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006056:Golgi Apparatus / Q000378:metabolism* / Q000648:ultrastructure; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000648:ultrastructure; D010766:Phosphorylation / Q000187:drug effects; D053764:Presenilin-1 / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects
chemical_list: D016229:Amyloid beta-Peptides; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D050505:Mutant Proteins; D053764:Presenilin-1; D047428:Protein Kinase Inhibitors; C523888:tamalin protein, mouse; D051360:Cyclin-Dependent Kinase 5
keywords: APP processing; GRASP55; Golgi stacking; amyloidogenic