Abstract

Project 1: Progesterone mechanisms of action in aging &Alzheimer's. In this Program Project, we jointly hypothesize that the sex steroid hormone progesterone promotes the brain's molecular, synaptic, cellular, and behavioral plasticity and reduces its vulnerability to the development of Alzheimer's disease (AD). We further hypothesize that the reproductive endocrine status, duration of ovariprivation and presence of AD related pathology regulates the plasticity response to ovarian steroids. Realizing the potential neural benefits of hormone therapy is constrained, at least in part, by our currently limited knowledge of the (1) basic neurobiology of progesterone, (2) the neural response to clinically relevant progestogens, (3) the complex modulatory interactions between progesterone and estrogen and (4) the impact of extended ovarian hormone privation and AD neuropathology on the brain's responsiveness to progesterone and estrogen. The objectives of Project 1 are to determine 1) the neuroprotective potential of progestogens;2) their associated mechanism of action including progesterone receptor isoform requirements;3) the impact of age and endocrine status on ovarian hormone-induced mitochondrial function;and 4) determine the impact of Alzheimer's disease pathology progression on gonadal hormone regulated mitochondrial function. To achieve these objectives, we have developed an interactive research plan that capitalizes on the expertise throughout the program project. Consistent with the Specific Aim structure of all projects within the Program, Specific Aim 1 will determine the direct effect of P Specific Aim 2 will determine the neuroprotective efficacy of clinically relevant progestins.
Specific Aim 3 will determine P4 regulation of E2-induced neuroprotection.
Specific Aim 4 will determine the impact of E2/P4 on mitochondrial function in rat models of human perimenopause and menopause.
Specific Aim 5 will determine the impact of E2/P4 on mitochondrial function in the 3xTgAD mouse model of AD. These studies will utilize both in vitro and in vivo models of neuronal function.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG026572-05
Application #
8078062
Study Section
Special Emphasis Panel (ZAG1)
Project Start
Project End
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
5
Fiscal Year
2010
Total Cost
$183,580
Indirect Cost

  Institution

Name
University of Southern California
Department
Type
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089

  Publications

Geifman, Nophar; Kennedy, Richard E; Schneider, Lon S et al. (2018) Data-driven identification of endophenotypes of Alzheimer's disease progression: implications for clinical trials and therapeutic interventions. Alzheimers Res Ther 10:4
Walters, Michelle J; Sterling, Joanna; Quinn, Crystal et al. (2018) Associations of lifestyle and vascular risk factors with Alzheimer's brain biomarker changes during middle age: a 3-year longitudinal study in the broader New York City area. BMJ Open 8:e023664
Mosconi, Lisa; Brinton, Roberta Diaz (2018) How would we combat menopause as an Alzheimer's risk factor? Expert Rev Neurother 18:689-691
Mosconi, Lisa; Walters, Michelle; Sterling, Joanna et al. (2018) Lifestyle and vascular risk effects on MRI-based biomarkers of Alzheimer's disease: a cross-sectional study of middle-aged adults from the broader New York City area. BMJ Open 8:e019362
Moser, V Alexandra; Uchoa, Mariana F; Pike, Christian J (2018) TLR4 inhibitor TAK-242 attenuates the adverse neural effects of diet-induced obesity. J Neuroinflammation 15:306
Berkowitz, C L; Mosconi, L; Rahman, A et al. (2018) Clinical Application of APOE in Alzheimer's Prevention: A Precision Medicine Approach. J Prev Alzheimers Dis 5:245-252
Gahm, Jin Kyu; Shi, Yonggang; Alzheimer’s Disease Neuroimaging Initiative (2018) Riemannian metric optimization on surfaces (RMOS) for intrinsic brain mapping in the Laplace-Beltrami embedding space. Med Image Anal 46:189-201
Riedel, Brandalyn C; Daianu, Madelaine; Ver Steeg, Greg et al. (2018) Uncovering Biologically Coherent Peripheral Signatures of Health and Risk for Alzheimer's Disease in the Aging Brain. Front Aging Neurosci 10:390
Scheyer, O; Rahman, A; Hristov, H et al. (2018) Female Sex and Alzheimer's Risk: The Menopause Connection. J Prev Alzheimers Dis 5:225-230
Mosconi, Lisa; Berti, Valentina; Quinn, Crystal et al. (2017) Sex differences in Alzheimer risk: Brain imaging of endocrine vs chronologic aging. Neurology 89:1382-1390

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