The long-term goal of our proposed research is to understand molecular basis of mitochondrial dysfunction Alzheimer's disease (AD) in pathogenesis and to develop neuroprotective strategies to delay or prevent the onset of AD. Increasing evidence suggests that amyloid beta (Ab), hyperphosphorylated tau and mitochondrial structural and functional abnormalities are critically involved in the loss of synapses and cognitive decline, in patients with Alzheimer's disease (AD). Several lines of evidence suggests that Ab and hyperphosphorylated tau are directly responsible for causing mitochondrial dysfunction and oxidative stress in AD pathogenesis. 1) Several studies found Ab and N-terminal tau in mitochondrial membranes and causing mitochondrial dysfunction in neurons affected by AD;2) recent studies found increased mRNA and protein levels of the mitochondrial fission genes and decreased fusion genes in AD postmortem and transgenic mouse models and cell-lines that express Ab, causing abnormal mitochondrial dynamics;3) several other studies found that Ab reduces total motile mitochondria, impairs mitochondrial axonal transport, particularly anterograde transport;inhibits synaptic ATP production;and causes synaptic degeneration in AD neurons and 4) further, GTPase protein, Drp1 interacted with Ab and hyperphosphorylated tau in neurons from AD patients and transgenic mouse models of Ab and tau. These findings lead to the hypothesis that the interaction of Drp1 with Ab and hyperphosphorylated tau triggers mitochondrial fission by enhancing Drp1 enzymatic activity and causes excessive mitochondrial fragmentation, and ultimate neuronal dysfunction selectively in AD neurons. The objectives of our application are 1) to determine whether Drp1 interactions with Ab and hyperphosphorylated tau increases with disease progression and pathogenesis;2) further how such interaction affects Drp1 enzymatic activity and mitochondrial morphology, distribution and function in AD neurons;3) in addition, whether partial loss of Drp1 decreases Ab and hyperphosphorylated tau-induced mitochondrial fragmentation, neuronal damage and synaptic dysfunction. The outcome of the proposed experiments in this application, will provide new insights in understanding the physiological relevance of interactions Drp1 with Ab, and phosphorylated tau in AD progression and pathogenesis and the outcome may have implications to develop mitochondrial therapeutics to reduce Ab and hyperphosphorylated tau-induced pathologies in AD patients.
Mitochondrial dysfunction is a major hallmark of Alzheimer's disease (AD). Mitochondria play an important role in neurons and maintain the balance of mitochondrial fission and fusion. The objective of the proposed research is to determine whether Drp1 interactions with amyloid beta and with hyperphosphorylated tau affect Drp1 enzymatic activity and alter mitochondrial morphology, distribution, and function in AD neurons, and whether partial loss of Drp1 decreases amyloid beta and hyperphosphorylated tau-induced mitochondrial fragmentation, neuronal damage, and synaptic dysfunction.
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|Reddy, P Hemachandra; Manczak, Maria; Yin, XiangLing (2017) Mitochondria-Division Inhibitor 1 Protects Against Amyloid-? induced Mitochondrial Fragmentation and Synaptic Damage in Alzheimer's Disease. J Alzheimers Dis 58:147-162|
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|Reddy, P Hemachandra (2017) Preface. Prog Mol Biol Transl Sci 146:xvii-xx|
|Bhatti, J S; Kumar, S; Vijayan, M et al. (2017) Therapeutic Strategies for Mitochondrial Dysfunction and Oxidative Stress in Age-Related Metabolic Disorders. Prog Mol Biol Transl Sci 146:13-46|
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