Multiple lines of evidence indicate that mitochondrial dysfunction plays a critical role in the pathogenesis of Alzheimer disease;however, the underlying molecular mechanism and its role in AD pathogenesis remain poorly understood. Mitochondria are dynamic organelles that undergo continuous fission and fusion. Our recent in vitro studies suggest that abnormal mitochondrial dynamics likely contributes to mitochondrial dysfunction and synaptic/neuronal dysfunction in AD. Based on these studies, we hypothesized that impaired balance in mitochondrial fission/fusion plays a critical role in the pathogenesis of AD by causing excessive mitochondrial fragmentation and redistribution as well as causes mitochondrial ultrastructural defects and dysfunction which in turn adversely affects neuronal functions including synaptic dysfunction and cognitive/behavioral deficits in AD. However, due to the limitation of in vitro cell culture models, it remains to be determined whether it is mitochondrial fragmentation or elongation that occurs in vivo since swollen mitochondrial in AD or APP mice may demonstrate increased size and/or length. Moreover, it also remains to be determined whether abnormal mitochondrial dynamics is causally involved in mitochondrial/synaptic dysfunction and cognitive deficits in APP mice in vivo. Our preliminary results demonstrated mitochondrial dysfunction, fragmented mitochondria, and decreased expression of mitochondrial fission/fusion proteins in the hippocampus of 3 month-old CRND8 APP transgenic mice, suggesting an altered mitochondrial dynamics early in the disease process. More importantly, we were able to enhance mitochondrial fusion in vivo by overexpressing Mfn2 expression in hippocampus, which enables us to address these critical gaps in our knowledge in vivo. Therefore, we propose to cross these Mfn2 mice with CRND8 APP transgenic mice and determine how normalization of mitochondrial dynamics will affect mitochondrial function, and neuronal/synaptic dysfunction and pathological/behavioral/cognitive deficits in CRND8 mice. The goal is to obtain a definite answer on the involvement of mitochondrial fragmentation or elongation in APP mice and to determine the causal role of mitochondrial dynamics in mitochondrial/neuronal dysfunction and cognitive/behavioral deficits in AD mouse models, which will also serve as a proof-of-concept study for Mfn2-directed therapy for AD. To complement the in vivo studies, we will determine the causal involvement of abnormal mitochondrial dynamics in Abeta-induced mitochondrial/neuronal function and further pursue mechanisms underlying Abeta-induced changes in mitochondrial dynamics and how Mfn2 overexpression rescues Abeta-induced mitochondrial deficits.
The balance of mitochondrial fission/fusion is critical for mitochondrial distribution and function which affects synaptic/neuronal function in AD cell models. In this application, we propose to investigate the causal involvement of mitochondrial fragmentation and abnormal distribution in the pathogenesis of AD in vivo and explore the underlying mechanisms.
|He, Liu; Jiang, Yuqi; Liu, Kai et al. (2018) Insights into the Impact of a Membrane-Anchoring Moiety on the Biological Activities of Bivalent Compounds As Potential Neuroprotectants for Alzheimer's Disease. J Med Chem 61:777-790|
|Jiang, Sirui; Nandy, Priya; Wang, Wenzhang et al. (2018) Mfn2 ablation causes an oxidative stress response and eventual neuronal death in the hippocampus and cortex. Mol Neurodegener 13:5|
|Yin, Jun; Zhao, Fanpeng; Chojnacki, Jeremy E et al. (2018) NLRP3 Inflammasome Inhibitor Ameliorates Amyloid Pathology in a Mouse Model of Alzheimer's Disease. Mol Neurobiol 55:1977-1987|
|Wang, Wenzhang; Yin, Jun; Ma, Xiaopin et al. (2017) Inhibition of mitochondrial fragmentation protects against Alzheimer's disease in rodent model. Hum Mol Genet 26:4118-4131|
|Wang, Wenzhang; Ma, Xiaopin; Zhou, Leping et al. (2017) A conserved retromer sorting motif is essential for mitochondrial DLP1 recycling by VPS35 in Parkinson's disease model. Hum Mol Genet 26:781-789|
|Zhou, Leping; Wang, Wenzhang; Hoppel, Charles et al. (2017) Parkinson's disease-associated pathogenic VPS35 mutation causes complex I deficits. Biochim Biophys Acta Mol Basis Dis 1863:2791-2795|
|Zhao, Fanpeng; Wang, Wenzhang; Wang, Chunyu et al. (2017) Mfn2 protects dopaminergic neurons exposed to paraquat both in vitro and in vivo: Implications for idiopathic Parkinson's disease. Biochim Biophys Acta Mol Basis Dis 1863:1359-1370|
|Liu, Yi; Zhu, Xiongwei (2017) Endoplasmic reticulum-mitochondria tethering in neurodegenerative diseases. Transl Neurodegener 6:21|
|Sharoar, M G; Shi, Q; Ge, Y et al. (2016) Dysfunctional tubular endoplasmic reticulum constitutes a pathological feature of Alzheimer's disease. Mol Psychiatry 21:1263-71|
|Zhang, Fan; Su, Bo; Wang, Chunyu et al. (2015) Posttranslational modifications of ?-tubulin in alzheimer disease. Transl Neurodegener 4:9|
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