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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
2P01AG027956-05A1
Application #
8436393
Study Section
Special Emphasis Panel (ZAG1-ZIJ-9 (O2))
Project Start
Project End
2017-11-30
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
5
Fiscal Year
2013
Total Cost
$261,492
Indirect Cost
$81,153
Name
University of North Texas
Department
Type
DUNS #
110091808
City
Fort Worth
State
TX
Country
United States
Zip Code
76107
Means, John C; Gerdes, Bryan C; Kaja, Simon et al. (2016) Caspase-3-Dependent Proteolytic Cleavage of Tau Causes Neurofibrillary Tangles and Results in Cognitive Impairment During Normal Aging. Neurochem Res 41:2278-88
Bukeirat, Mimi; Sarkar, Saumyendra N; Hu, Heng et al. (2016) MiR-34a regulates blood-brain barrier permeability and mitochondrial function by targeting cytochrome c. J Cereb Blood Flow Metab 36:387-92
Engler-Chiurazzi, E B; Singh, M; Simpkins, J W (2016) Reprint of: From the 90׳s to now: A brief historical perspective on more than two decades of estrogen neuroprotection. Brain Res 1645:79-82
Sun, Jiahong; Ren, Xuefang; Qi, Wen et al. (2016) Geissoschizine methyl ether protects oxidative stress-mediated cytotoxicity in neurons through the 'Neuronal Warburg Effect'. J Ethnopharmacol 187:249-58
Engler-Chiurazzi, E B; Singh, M; Simpkins, J W (2016) From the 90's to now: A brief historical perspective on more than two decades of estrogen neuroprotection. Brain Res 1633:96-100
Engler-Chiurazzi, E B; Brown, C M; Povroznik, J M et al. (2016) Estrogens as neuroprotectants: Estrogenic actions in the context of cognitive aging and brain injury. Prog Neurobiol :
Petrone, Ashley B; O'Connell, Grant C; Regier, Michael D et al. (2016) The Role of Arginase 1 in Post-Stroke Immunosuppression and Ischemic Stroke Severity. Transl Stroke Res 7:103-10
Sarkar, S; Jun, S; Rellick, S et al. (2016) Expression of microRNA-34a in Alzheimer's disease brain targets genes linked to synaptic plasticity, energy metabolism, and resting state network activity. Brain Res 1646:139-51
Hu, Heng; Doll, Danielle N; Sun, Jiahong et al. (2016) Mitochondrial Impairment in Cerebrovascular Endothelial Cells is Involved in the Correlation between Body Temperature and Stroke Severity. Aging Dis 7:14-27
Strong, Randy; Miller, Richard A; Antebi, Adam et al. (2016) Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an α-glucosidase inhibitor or a Nrf2-inducer. Aging Cell 15:872-84

Showing the most recent 10 out of 111 publications