title: Amyloid β oligomers elicit mitochondrial transport defects and fragmentation in a time-dependent and pathway-specific manner.
abstract: Small oligomeric forms of amyloid-β (Aβ) are believed to be the culprit for declined brain functions in AD in part through their impairment of neuronal trafficking and synaptic functions. However, the precise cellular actions of Aβ oligomers and underlying mechanisms in neurons remain to be fully defined. Previous studies have identified mitochondria as a major target of Aβ toxicity contributing to early cognitive decline and memory loss in neurodegenerative diseases including Alzheimer's disease (AD). In this study, we report that Aβ oligomers acutely elicit distinct effects on the transport and integrity of mitochondria. We found that acute exposure of hippocampal neurons to Aβ oligomers from either synthetic peptides or AD brain homogenates selectively impaired fast transport of mitochondria without affecting the movement of late endosomes and lysosomes. Extended exposure of hipoocampal neurons to Aβ oligomers was found to result in mitochondrial fragmentation. While both mitochondrial effects induced by Aβ oligomers can be abolished by the inhibition of GSK3β, they appear to be independent from each other. Aβ oligomers impaired mitochondrial transport through HDAC6 activation whereas the fragmentation involved the GTPase Drp-1. These results show that Aβ oligomers can acutely disrupt mitochondrial transport and integrity in a time-dependent and pathway-specific manner. These findings thus provide new insights into Aβ-induced mitochondrial defects that may contribute to neuronal dysfunction and AD pathogenesis.
authors.affiliation: Department of Cell Biology, Emory University School of Medicine, 615 Michael Street, Atlanta, GA, 30322, USA.|Center for Neurodegenerative Diseases, Emory University School of Medicine, Atlanta, GA, 30322, USA.
authors.forename: Yanfang
authors.initials: Y
authors.lastname: Rui
authors.affiliation: Department of Cell Biology, Emory University School of Medicine, 615 Michael Street, Atlanta, GA, 30322, USA. james.zheng@emory.edu.|Department of Neurology, Emory University School of Medicine, Atlanta, GA, 30322, USA. james.zheng@emory.edu.|Center for Neurodegenerative Diseases, Emory University School of Medicine, Atlanta, GA, 30322, USA. james.zheng@emory.edu.
authors.forename: James Q
authors.initials: JQ
authors.lastname: Zheng
mesh_terms: D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D003712:Dendrites / Q000187:drug effects / Q000378:metabolism; D034281:Dynamins / Q000378:metabolism; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D008954:Models, Biological; D055503:Protein Multimerization; D051381:Rats; D013997:Time Factors
chemical_list: D016229:Amyloid beta-Peptides; C545556:HDAC6 protein, rat; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; C519851:Dnm1l protein, rat; D034281:Dynamins
keywords: Alzheimer’s disease; Drp-1; Fragmentation; GSK3β; HDAC6; Hippocampus; Transport