During the previous funding period, we made a number of fundamental observations relative to the mechanism of action of estrogens on mitochondria that guide the aims of the present proposal. We have evidence that the bioenergetic crisis seen during normal brain aging and in AD is caused by mitochondrial structure, function and mobility dysfunctions that leads to a breakdown in synaptic integrity resulting in cognitive decline that characterizes both aging and AD. The present continuation of this grant will further assess the mechanism(s) of effects of estrogens on mitochondria and determine if these effects occur in vivo and in post-mortem samples from women. We will address 4 specific aims.
Specific Aim 1 will determine if pharmacological antagonism or genetic reduction in the PKA/DRP1 pathway leads to a loss of synaptic integrity, mitochondrial fission and immobility, and bioenergetic decline in primary hippocamal neurons.
Specific Aim 2 will determine if ovariectomy for 2, 12 or 20 weeks compromises the PKA/DRP1 pathway leading to synaptic loss and mitochondrial dysfunction and if these deficits can be restored by E2, an ER(3 agonist, DPN, or P4 treatment for 6 weeks, in vivo.
Specific Aim 3 will determine if age and post-ovariectomy duration, changes the synaptoneurosome response to E2, DPN or P4.
Specific Aim 4 will determine if therapy with DPN improves PKA/DRP1 pathway function, thereby ameliorating loss of synaptic integrity, mitochondrial immobility and fragmentation seen in a 5XFAD mice model. For all of the aims, we will assess DRPI phosphorylation state, a panel of pre- and post-synaptic markers, and a panel of bioenergetic measures.
For aims 1 and 4, we will conduct a detailed assessment of mitochnodrial fragmentation and mobility. Successful completion of these proposed studies could lead to new understanding of estrogen targets in the brain as well as potential new therapies for age-related cognitive decline and AD.

Public Health Relevance

The present application will test the hypothesis that estrogen signaling through mitochondrial ERp-PKA DRP-1 pathway may in part or entirely prevent age- and AD-related deficits in mitochondrial structure, function and movement and thereb preserve synaptic function. Successful completion of these proposed studies could lead to new understanding of estrogen targets in the brain as well as potential new therapies for age-related cognitive decline and AD.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
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Special Emphasis Panel (ZAG1-ZIJ-9)
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University of North Texas
Fort Worth
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Kaja, Simon; Sumien, Nathalie; Shah, Vidhi V et al. (2015) Loss of Spatial Memory, Learning, and Motor Function During Normal Aging Is Accompanied by Changes in Brain Presenilin 1 and 2 Expression Levels. Mol Neurobiol 52:545-54
Petrone, Ashley B; Simpkins, James W; Barr, Taura L (2014) 17?-estradiol and inflammation: implications for ischemic stroke. Aging Dis 5:340-5
Li, W; Huang, R; Chen, Z et al. (2014) PTEN degradation after ischemic stroke: a double-edged sword. Neuroscience 274:153-61
Chen, Fangfang; Qi, Wen; Sun, Jiahong et al. (2014) Urinary metabolites of isorhynchophylline in rats and their neuroprotective activities in the HT22 cell assay. Fitoterapia 97:156-63
Payne, Andrew J; Kaja, Simon; Naumchuk, Yuliya et al. (2014) Antioxidant drug therapy approaches for neuroprotection in chronic diseases of the retina. Int J Mol Sci 15:1865-86
Cunningham, Rebecca L; Singh, Meharvan; O'Bryant, Sid E et al. (2014) Oxidative stress, testosterone, and cognition among Caucasian and Mexican-American men with and without Alzheimer's disease. J Alzheimers Dis 40:563-73
Kaja, Simon; Naumchuk, Yuliya; Grillo, Stephanie L et al. (2014) Differential up-regulation of Vesl-1/Homer 1 protein isoforms associated with decline in visual performance in a preclinical glaucoma model. Vision Res 94:16-23
Petrone, Ashley B; Gatson, Joshua W; Simpkins, James W et al. (2014) Non-feminizing estrogens: a novel neuroprotective therapy. Mol Cell Endocrinol 389:40-7
Xie, Luokun; Sun, Fen; Wang, Jixian et al. (2014) mTOR signaling inhibition modulates macrophage/microglia-mediated neuroinflammation and secondary injury via regulatory T cells after focal ischemia. J Immunol 192:6009-19
Faure, Lionel; Nagarajan, Subbiah; Hwang, Hyeondo et al. (2014) Synthesis of phenoxyacyl-ethanolamides and their effects on fatty acid amide hydrolase activity. J Biol Chem 289:9340-51

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