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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13041-016-0261-z) contains supplementary material, which is available to authorized users.
Highlights
Alzheimer’s disease (AD) is a progressive neurodegenerative brain disorder that is characterized by two hallmarks: intracellular neurofibrillary tangles and extracellular amyloid-β (Aβ) plaques in the regions of the brain that are responsible for learning and memory
We found that exposure of cultured hippocampal neurons to Aβ oligomers (Aβ-O) (1 μM total Aβ, ~100 nM of oligomers) markedly inhibited the fast transport of mitochondria without affecting late endosomes/lysosomes of the same neurons, as evidenced by the movement tracings from the 5-min time-lapse sequences (Fig. 1b)
We found that acute exposure of hippocampal neurons to Aβ oligomers did not affect the expression of histone deacetylase 6 (HDAC6) (Additional file 1: Figure S6 a and b), it did appear to increase the activities of Histone deacetylase (HDAC) in the cytosol and mitochondria as measured biochemically using the HDAC activity fluorometric assay kit (Additional file 1: Figure S6c)
Summary
Alzheimer’s disease (AD) is a progressive neurodegenerative brain disorder that is characterized by two hallmarks: intracellular neurofibrillary tangles and extracellular amyloid-β (Aβ) plaques in the regions of the brain that are responsible for learning and memory. Rui and Zheng Molecular Brain (2016) 9:79 to the specific subcellular regions via microtubule (MT)-based fast transport [6, 7]. Mitochondria are seen accumulated at the pre- and post-synaptic sites where they function in synaptic transmission and plasticity [8,9,10,11,12]. Such subcellular localization of mitochondria involves spatiotemporal regulation of MT-based motors as well as interactions with other cytoskeletal structures such as the actin cytoskeleton and intermediate filaments [6]. Timely and proper delivery of new mitochondria from the cell body is important to support the health and function of mitochondria in neurons
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