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Short-term estradiol use in middle-age: implications for female cognitive aging

Award Number: RF1AG041374
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2012
PERIOD OF PERFORMANCE END DATE: 08/31/2023

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Short-term estradiol use in middle-age: implications for female cognitive aging - Abstract of Proposed Research Administration of estrogens begun during a critical window near menopause is hypothesized to prevent or delay age-associated cognitive decline and Alzheimer's disease (AD) and related dementias. However, due to potential health risks women often limit use of estrogen therapy to a few years to treat menopausal symptoms. The long-term consequences for the brain, cognitive aging, and risk of dementia of short-term use of estrogens are unknown. The long-term goal of the research currently supported is to determine the consequences for the female brain and for female cognitive aging of short-term exposure to estrogens during middle-age such as that used by women during the menopausal transition. [Please see full abstract of current grant at the end of Research Strategy.] Our work has shown that short-term exposure to estradiol, the primary estrogen, following ovariectomy in aging female rodents provides lasting, likely permanent, cognitive benefits that extend well beyond the period of exposure and results in concomitant lasting, likely permanent increases in levels of estrogen receptor (ER) α in the hippocampus, a brain area critical for memory. Furthermore, we have demonstrated that increased levels or availability of ERs in the hippocampus results in enhanced memory in the absence of ovarian or endogenously administered estrogens. The importance of ERα to cognitive aging is highlighted by results of studies that show a relationship between levels of wild-type and polymorphisms of ERα with development of cognitive impairment in women, including risk of AD. The currently proposed research aims to expand on our present work on female cognitive aging to include investigation of estradiol and estrogen receptor impacts on the hippocampus and memory in a new mouse model of AD, Aβ precursor protein (APP) knock-in mice, AppNL-G-F/NL-G-F. The model exhibits typical Aβ pathology and memory impairment in an age-dependent manner without APP overexpression, the strategy used in most of the other available mouse models of AD. We will specifically investigate the ability of estradiol treatments that we have shown to enhance hippocampal levels of ERα and memory to impact memory impairments and Aβ in these APP knock-in mice. Two specific aims will be tested: 1) To determine if manipulating estradiol levels in female APP knock-in mice before development of Aβ pathology can impact memory and / or pathology in the hippocampus; 2) To determine if manipulation of estradiol levels after development of pathology can impact function and / or further progression of Aβ pathology. Results of these pilot projects will provide the basis of our future investigation into how short-term midlife estradiol use impacts long-term risk for AD.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2019	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Aging Research	000	6	2/20/2024	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2019	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Aging Research	001	6	10/21/2022	SUPPLEMENT FOR EXPANSION	$0
2023	2019	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Aging Research	002	6	10/27/2022	SUPPLEMENT FOR EXPANSION	$0
2023	2018	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Aging Research	000	6	10/20/2022	COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $376,250 )
2019	2019	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Aging Research	000	6	8/29/2019	SUPPLEMENT FOR EXPANSION	$376,250
														Subtotal = $376,250

Issue Date FY: 2018 ( Subtotal = $1,893,125 )
2018	2018	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Aging Research	002	6	9/20/2018	COMPETING CONTINUATION	$0
2018	2018	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Aging Research	001	6	9/15/2018	COMPETING CONTINUATION	$1,516,875
2018	2018	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Aging Research	000	6	3/16/2018	COMPETING CONTINUATION	$376,250
														Subtotal = $1,893,125

Grand Total All Awards = $2,269,375

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Short-term estradiol use in middle-age: implications for female cognitive aging

Award Number: RF1AG041374

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/01/2012

PERIOD OF PERFORMANCE END DATE: 08/31/2023

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