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

Small oligomeric forms of amyloid-[beta] (A[beta]) 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 A[beta] oligomers and underlying mechanisms in neurons remain...

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Bibliographic Details
Published in:Molecular brain 2016-08, Vol.9 (1)
Main Authors: Rui, Yanfang, Zheng, James Q
Format: Article
Language:English
Subjects:
Alzheimer's disease
Amyloid beta-protein
Brain research
Mitochondria
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Summary:Small oligomeric forms of amyloid-[beta] (A[beta]) 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 A[beta] oligomers and underlying mechanisms in neurons remain to be fully defined. Previous studies have identified mitochondria as a major target of A[beta] toxicity contributing to early cognitive decline and memory loss in neurodegenerative diseases including Alzheimer's disease (AD). In this study, we report that A[beta] oligomers acutely elicit distinct effects on the transport and integrity of mitochondria. We found that acute exposure of hippocampal neurons to A[beta] 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 A[beta] oligomers was found to result in mitochondrial fragmentation. While both mitochondrial effects induced by A[beta] oligomers can be abolished by the inhibition of GSK3[beta], they appear to be independent from each other. A[beta] oligomers impaired mitochondrial transport through HDAC6 activation whereas the fragmentation involved the GTPase Drp-1. These results show that A[beta] oligomers can acutely disrupt mitochondrial transport and integrity in a time-dependent and pathway-specific manner. These findings thus provide new insights into A[beta]-induced mitochondrial defects that may contribute to neuronal dysfunction and AD pathogenesis. Keywords: Alzheimer's disease, Transport, Fragmentation, Hippocampus, HDAC6, Drp-1, GSK3[beta]
ISSN:1756-6606
1756-6606
DOI:10.1186/s13041-016-0261-z