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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG042178-01A1
Application #
8451085
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Refolo, Lorenzo
Project Start
2012-09-30
Project End
2017-04-30
Budget Start
2012-09-30
Budget End
2013-04-30
Support Year
1
Fiscal Year
2012
Total Cost
$439,653
Indirect Cost
$188,423
Name
Oregon Health and Science University
Department
Other Basic Sciences
Type
Other Domestic Higher Education
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
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Vijayan, M; Kumar, S; Bhatti, J S et al. (2017) Molecular Links and Biomarkers of Stroke, Vascular Dementia, and Alzheimer's Disease. Prog Mol Biol Transl Sci 146:95-126
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
Kandimalla, Ramesh; Reddy, P Hemachandra (2017) Therapeutics of Neurotransmitters in Alzheimer's Disease. J Alzheimers Dis 57:1049-1069
Reddy, A P; Reddy, P H (2017) Mitochondria-Targeted Molecules as Potential Drugs to Treat Patients With Alzheimer's Disease. Prog Mol Biol Transl Sci 146:173-201
Reddy, P H; Williams, J; Smith, F et al. (2017) MicroRNAs, Aging, Cellular Senescence, and Alzheimer's Disease. Prog Mol Biol Transl Sci 146:127-171
Rajmohan, Ravi; Anderson, Ronald C; Fang, Dan et al. (2017) White Matter Deterioration May Foreshadow Impairment of Emotional Valence Determination in Early-Stage Dementia of the Alzheimer Type. Front Aging Neurosci 9:37
Williams, Justin; Smith, Flint; Kumar, Subodh et al. (2017) Are microRNAs true sensors of ageing and cellular senescence? Ageing Res Rev 35:350-363
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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