Alzheimer disease (AD) involves infiammatory processes at many levels. Because ovarian steroids show many anfi-infiammatory activities, hormone therapy (HT) in AD may involve inflammatory pathways activated during the menopause transitions when hormonal deficits emerge progressively. We propose rodent models of perimenopausal stages to analyze inflammatory changes in brain regions vulnerable to AD, with a focus on aging Sprague-Dawley rats. The 3xTg-AD mouse model will be used to examine specific hypothesis about relationships of inflammation during aging to human familial AD. These models will be examined for responsiveness to HT, according to the KEEPS clinical model of E2 + cyclic P4. We will examine E2-P4 effects on microglial-astrocyte interacfions in infiammafion and in neurotrophic effects.
Specific Aim 1 : Infiammatory profile in rat and mouse models of human perimenopause and menopause stages (Animal Core B). 1.1. Inflammatory gene expression and bioinformafic analysis in hippocampus and cerebral cortex of aging rats and mice from different menopausal stages (Analytic Core). 1.2. In vitro modeling of perimenopausal inflammatory changes, using primary glial cultures originated from perimenopausal rats. 1.3. Bioenergefics of glia cultured from perimenopausal rats (with Project 1).
Specific Aim 2 : Neurodegenerative mechanisms in perimenopausal infiammatory changes, using glial- neuronal co-cultures. 2.1. Role of infiammatory genes in glial-mediated neuronal support. 2.2, Role of estrogen receptors (ERa:ER|3) in regulating perimenopausal glial inflammatory phenotypes. Astrocytes from aging rats are deficient in neurotrophic support, in which one factor is altered ratio of estrogen receptors ERa:ERp (pilot data). 2.3. Role of progesterone receptors (PR) in regulafing perimenopausal glial infiammatory changes, with a focus on Pgmrcl (pilot data). 2.4. Role of glial N0S2 in neuronal mitochondria dysfunction (with Project 1). 2.5. Obesity-infiammation interactions (with Project 3).
Specific Aim 3 : Effects of perimenopausal HT on brain cell infiammation. Following the KEEPS model of E2 + cyclic P4, rats and 3xTg-AD mice will be given HT during perimenopausal cycling stages. 3.1. Infiammatory gene expression and bioinformafics (Analytic Core). 3.2. In vitro models of infiammatory changes, using primary glial from aging rat cerebral cortex. 3.3. Bioenergefics of glial cultures (with Project 1).

Public Health Relevance

Our primary goal is to develop animal models for the perimenopause transition to analyze brain cell sensitivity to ovarian steroids. Findings are relevant to optimization of hormone therapy to protect against normal age-related cognitive decline, multi-infarct demenfia and Alzheimers Diease

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAG1-ZIJ-8)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Southern California
Los Angeles
United States
Zip Code
Pike, Christian J (2017) Sex and the development of Alzheimer's disease. J Neurosci Res 95:671-680
Kurita, Keiko; Henderson, Victor W; Gatz, Margaret et al. (2016) Association of bilateral oophorectomy with cognitive function in healthy, postmenopausal women. Fertil Steril 106:749-756.e2
Finch, Caleb E; Shams, Sara (2016) Apolipoprotein E and Sex Bias in Cerebrovascular Aging of Men and Mice. Trends Neurosci 39:625-37
Uchoa, Mariana F; Moser, V Alexandra; Pike, Christian J (2016) Interactions between inflammation, sex steroids, and Alzheimer's disease risk factors. Front Neuroendocrinol 43:60-82
Karim, Roksana; Dang, Ha; Henderson, Victor W et al. (2016) Effect of Reproductive History and Exogenous Hormone Use on Cognitive Function in Mid- and Late Life. J Am Geriatr Soc 64:2448-2456
Yin, Fei; Sancheti, Harsh; Patil, Ishan et al. (2016) Energy metabolism and inflammation in brain aging and Alzheimer's disease. Free Radic Biol Med 100:108-122
Riedel, Brandalyn C; Thompson, Paul M; Brinton, Roberta Diaz (2016) Age, APOE and sex: Triad of risk of Alzheimer's disease. J Steroid Biochem Mol Biol 160:134-47
Finch, Caleb E; McMahon, Andrew P (2016) Stem cells for all ages, yet hostage to aging. Stem Cell Investig 3:11
Rettberg, Jamaica R; Dang, Ha; Hodis, Howard N et al. (2016) Identifying postmenopausal women at risk for cognitive decline within a healthy cohort using a panel of clinical metabolic indicators: potential for detecting an at-Alzheimer's risk metabolic phenotype. Neurobiol Aging 40:155-63
Cacciottolo, Mafalda; Christensen, Amy; Moser, Alexandra et al. (2016) The APOE4 allele shows opposite sex bias in microbleeds and Alzheimer's disease of humans and mice. Neurobiol Aging 37:47-57

Showing the most recent 10 out of 91 publications