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 #
5R01AG042178-05
Application #
8841650
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Yang, Austin Jyan-Yu
Project Start
2012-09-30
Project End
2017-04-30
Budget Start
2015-05-01
Budget End
2016-04-30
Support Year
5
Fiscal Year
2015
Total Cost
$365,294
Indirect Cost
$123,377
Name
Texas Tech University
Department
Type
Schools of Medicine
DUNS #
609980727
City
Lubbock
State
TX
Country
United States
Zip Code
79430
Reddy, P Hemachandra; Yin, XiangLing; Manczak, Maria et al. (2018) Mutant APP and amyloid beta-induced defective autophagy, mitophagy, mitochondrial structural and functional changes and synaptic damage in hippocampal neurons from Alzheimer's disease. Hum Mol Genet 27:2502-2516
Vijayan, Murali; Kumar, Subodh; Yin, Xiangling et al. (2018) Identification of novel circulatory microRNA signatures linked to patients with ischemic stroke. Hum Mol Genet 27:2318-2329
Reddy, P Hemachandra; Manczak, Maria; Yin, Xiangling et al. (2018) Protective Effects of Indian Spice Curcumin Against Amyloid-? in Alzheimer's Disease. J Alzheimers Dis 61:843-866
Kumar, Subodh; Reddy, P Hemachandra (2018) MicroRNA-455-3p as a Potential Biomarker for Alzheimer's Disease: An Update. Front Aging Neurosci 10:41
Reddy, P Hemachandra; Manczak, Maria; Yin, XiangLing et al. (2018) Synergistic Protective Effects of Mitochondrial Division Inhibitor 1 and Mitochondria-Targeted Small Peptide SS31 in Alzheimer's Disease. J Alzheimers Dis 62:1549-1565
Pradeepkiran, Jangampalli Adi; Reddy, Arubala P; Reddy, P Hemachandra (2018) Pharmacophore-based models for therapeutic drugs against phosphorylated tau in Alzheimer's disease. Drug Discov Today :
Kandimalla, Ramesh; Manczak, Maria; Yin, Xiangling et al. (2018) Hippocampal phosphorylated tau induced cognitive decline, dendritic spine loss and mitochondrial abnormalities in a mouse model of Alzheimer's disease. Hum Mol Genet 27:30-40
Kumar, Subodh; Vijayan, Murali; Reddy, P Hemachandra (2017) MicroRNA-455-3p as a potential peripheral biomarker for Alzheimer's disease. Hum Mol Genet 26:3808-3822
Rajmohan, Ravi; Anderson, Ronald C; Fang, Dan et al. (2017) Lower Activation in Frontal Cortex and Posterior Cingulate Cortex Observed during Sex Determination Test in Early-Stage Dementia of the Alzheimer Type. Front Aging Neurosci 9:156
Reddy, P Hemachandra; Tonk, Sahil; Kumar, Subodh et al. (2017) A critical evaluation of neuroprotective and neurodegenerative MicroRNAs in Alzheimer's disease. Biochem Biophys Res Commun 483:1156-1165

Showing the most recent 10 out of 59 publications