Amyloid beta oligomers elicit mitochondrial transport defects and fragmentation in a time-dependent and pathway-specific manner

• Type of Material: Article
• Authors: Yanfang Rui, Emory University; James Zheng, Emory University
• Language: English
• Date: 2016-08-17
• Publisher: BioMed Central
• Publication Version: Final Published Version
• Copyright Statement: © 2016 The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1186/s13041-016-0261-z
• Title of Journal or Parent Work: Molecular Brain
• ISSN: 1756-6606
• Volume: 9
• Issue: 1
• Start Page: 79
• End Page: 79
• Grant/Funding Information: This research was supported in part by grants from the National Institutes of Health (GM083889 and MH104632), a pilot grant from Emory Alzheimer’s Disease Resource Center (ADRC P50 AG025688), a NINDS core facilities grant (P30NS055077) to the Neuronal Imaging Core of Emory Neuroscience, and a postdoctoral fellowship from the Ellison Medical Foundation/American Federation for Aging Research to YR.
• Keywords: ACETYLATION; TRAFFICKING; DRP1 PHOSPHORYLATION; Alzheimer's disease; Neurosciences & Neurology; Science & Technology; Fragmentation; ALZHEIMERS-DISEASE; ALPHA-TUBULIN; Hippocampus; Neurosciences; HDAC6; CULTURED HIPPOCAMPAL-NEURONS; AXONAL-TRANSPORT; NEURODEGENERATIVE DISEASES; GSK3 beta; SYNAPSES; Life Sciences & Biomedicine; Drp-1; Transport
• Research Categories: Biology, Cell; Biology, Microbiology; Biology, Neuroscience

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.