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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Nguyen, Trinh; Su, Chang; Singh, Meharvan (2018) Let-7i inhibition enhances progesterone-induced functional recovery in a mouse model of ischemia. Proc Natl Acad Sci U S A 115:E9668-E9677
Izurieta Munoz, Haydee; Gonzales, Eric B; Sumien, Nathalie (2018) Effects of creatine supplementation on nociception in young male and female mice. Pharmacol Rep 70:316-321
Montgomery, Christa L; Johnson, Heather M; Johnston, Thomas P et al. (2018) Mechanisms Underlying Early-Stage Changes in Visual Performance and Retina Function After Experimental Induction of Sustained Dyslipidemia. Neurochem Res 43:1500-1510
Grillo, Stephanie L; Montgomery, Christa L; Johnson, Heather M et al. (2018) Quantification of Changes in Visual Function During Disease Development in a Mouse Model of Pigmentary Glaucoma. J Glaucoma 27:828-841
Mock, J Thomas; Knight, Sherilynn G; Vann, Philip H et al. (2018) Gait Analyses in Mice: Effects of Age and Glutathione Deficiency. Aging Dis 9:634-646
Grillo, Michael A; Grillo, Stephanie L; Gerdes, Bryan C et al. (2018) Control of Neuronal Ryanodine Receptor-Mediated Calcium Signaling by Calsenilin. Mol Neurobiol :
Kaja, Simon; Payne, Andrew J; Naumchuk, Yuliya et al. (2017) Quantification of Lactate Dehydrogenase for Cell Viability Testing Using Cell Lines and Primary Cultured Astrocytes. Curr Protoc Toxicol 72:2.26.1-2.26.10
Gonzales, Eric B; Sumien, Nathalie (2017) Acidity and Acid-Sensing Ion Channels in the Normal and Alzheimer's Disease Brain. J Alzheimers Dis 57:1137-1144
Engler-Chiurazzi, E B; Brown, C M; Povroznik, J M et al. (2017) Estrogens as neuroprotectants: Estrogenic actions in the context of cognitive aging and brain injury. Prog Neurobiol 157:188-211
Engler-Chiurazzi, Elizabeth B; Covey, Douglas F; Simpkins, James W (2017) A novel mechanism of non-feminizing estrogens in neuroprotection. Exp Gerontol 94:99-102

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