Abstract

This project addresses the cellular mechanisms underlying the dual actions of estrogen in women with Alzheimer's Disease, i.e., the improvement of the cognitive deficits and the reduced incidence of AD in women with estrogen replacement therapy. These effects of estrogen suggest that estrogen or some equine estrogen constituent acts as a cognitive enhancer and/oras a neuroprotective agent. These hypothesis will be tested in in vitro models of synaptic plasticity and neurodegeneration. Long-term potentiation (LTP) is widely considered to represent a cellular mechanism for information storage and compounds modulating LTP have been found to modulate learning and memory processes. LTP induction and expression are critically dependent on 2 classes of inotropic receptors, the NMDA and the AMPA receptors, respectively.
Specific Aims 1 and 2 will therefore be directed at determining the effects of acute and chronic estrogen treatment of hippocampal slices maintained in culture for several; weeks on the characteristics of AMPA and NMDA receptors and on the properties of LTP. Treatment of cultured hippocampal slices with excitotoxin or beta- amyloid peptide (betaAP) produces selective neuronal damage which exhibits several features of neuronal death occurring in AD.
Specific Aims 3 and 4 will therefore evaluate the neuroprotective effects of estrogen in these models. Effects of estrogen in these in vitro systems will be compared with its effects in cultures of dissociated neurons as well as in in vivo models of synaptic plasticity and neurodegeneration.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
1P01AG014751-02
Application #
6267747
Study Section
Project Start
1998-08-01
Project End
1999-07-31
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost

  Institution

Name
University of Southern California
Department
Type
DUNS #
041544081
City
Los Angeles
State
CA
Country
United States
Zip Code
90089

  Publications

Finch, Caleb E; Beltrán-Sánchez, Hiram; Crimmins, Eileen M (2014) Uneven futures of human lifespans: reckonings from Gompertz mortality rates, climate change, and air pollution. Gerontology 60:183-8
Baudry, M; Bi, X; Aguirre, C (2013) Progesterone-estrogen interactions in synaptic plasticity and neuroprotection. Neuroscience 239:280-94
Kim, Soyun; Wang, Miao; Lee, Amy S et al. (2011) Impaired eyeblink conditioning in 78 kDa-glucose regulated protein (GRP78)/immunoglobulin binding protein (BiP) conditional knockout mice. Behav Neurosci 125:404-11
Kim, Soyun; Thompson, Richard F (2011) c-Fos, Arc, and stargazin expression in rat eyeblink conditioning. Behav Neurosci 125:117-23
Connor, S; Bloomfield, J; LeBoutillier, J C et al. (2009) Eyeblink conditioning leads to fewer synapses in the rabbit cerebellar cortex. Behav Neurosci 123:856-62
Zadran, Sohila; Qin, Qingyu; Bi, Xiaoning et al. (2009) 17-Beta-estradiol increases neuronal excitability through MAP kinase-induced calpain activation. Proc Natl Acad Sci U S A 106:21936-41
Dominguez, Reymundo; Hu, Eric; Zhou, Miou et al. (2009) 17beta-estradiol-mediated neuroprotection and ERK activation require a pertussis toxin-sensitive mechanism involving GRK2 and beta-arrestin-1. J Neurosci 29:4228-38
Thompson, Richard F (2009) Habituation: a history. Neurobiol Learn Mem 92:127-34
Micevych, Paul; Dominguez, Reymundo (2009) Membrane estradiol signaling in the brain. Front Neuroendocrinol 30:315-27
Brinton, Roberta Diaz (2009) Estrogen-induced plasticity from cells to circuits: predictions for cognitive function. Trends Pharmacol Sci 30:212-22

Showing the most recent 10 out of 54 publications