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

作者：Rui Yanfang; Zheng James Q^*

来源：Molecular Brain, 2016, 9(1): 79.

DOI：10.1186/s13041-016-0261-z

• Alzheimer's disease
• Transport
• Fragmentation
• Hippocampus
• HDAC6
• Drp-1
• GSK3 beta

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.

• 出版日期2016-8-17