Alzheimer's disease (AD) is characterized at post-mortem examination by high densities of -amyloid (A)-containing plaques and extensive neurogliosis in cortical brain regions, with severe loss of neurons, including the pyramidal neurons in the CA sub-regions of the hippocampus and noradrenergic neurons in the locus coeruleus (LC). AD is the most common cause of elderly dementia and women have a higher incidence of AD than men. The gradual loss of sex steroid hormones may contribute to age associated cognitive decline. A neuroprotective role of estrogens in murine models has been established. Specifically, 17-?-estradiol has been shown to stimulate enhanced synaptic plasticity, neurite growth, hippocampal neurogenesis and long-term potentiation. However, its effects on peripheral targets in humans limit the usefulness of ?-E2 as a potential therapy. Negative outcomes from the large Women's Health Initiative Memory Study (WHIMS), a clinical study using ?-E2 highlight the dire need to analyze non-feminizing estrogens. Recently, we discovered that 17-?-estradiol (?-E2), an isomer of 17?-estradiol, appear to mitigate the severiy of neuron loss, amyloid burden, and neuroglial proliferation in adult dtg APP/PS1 mice. To begin to address this hypothesis in-vivo, we propose to identify mechanisms for the neuroprotective effects of ?-E2 in APOE knock in (APOE3 and APOE4) and 5x FAD mice. Using equal numbers of both male and female mice, we will deliver ?E2 over sixty days via subcutaneous pellets. Sacrifice and brain removal will follow to identify if neuroprotective effects of ?E2 are mediated in a sex and/or apoE genotype dependent manner. Endpoints for these studies will be computerized stereology to quantify neuron loss in CA1 and LC, amyloid burden and neuroglial proliferation in the hippocampal formation; and enzyme-linked immunoassays to quantify levels of A peptides and pro-inflammatory cytokines in hippocampal molecular layers. Taken together, these experiments will provide perhaps the most direct in-vivo assessment of cellular sites for ?E2's neuroprotective effects in APOE knock-in (APOE3 and APOE4) and 5x FAD mice. Results will assess whether ?E2 deserves further study as a potential strategy for the therapeutic management of AD in middle-aged and elderly men and women.

Public Health Relevance

Alzheimer's disease is a major source of emotional suffering to afflicted patients and their families, and an enormous economic burden to society. Using the most advanced technology to date, the proposed study will evaluate the therapeutic potential of ?-estradiol on a unique model of Alzheimer's pathology in mice. These experiments will help to develop novel translational strategies for the treatment of these patients.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Small Research Grants (R03)
Project #
1R03AG049288-01A1
Application #
9086498
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Yang, Austin Jyan-Yu
Project Start
2016-05-01
Project End
2018-04-30
Budget Start
2016-05-01
Budget End
2017-04-30
Support Year
1
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Howard University
Department
Physiology
Type
Schools of Medicine
DUNS #
056282296
City
Washington
State
DC
Country
United States
Zip Code
20059