Alzheimer's disease progression and neuroimmune activity in a mouse model of oral contraceptive exposure
Active Project Grant Awarded Last action
- Award ID
- F31AG104361
- Recipient
-
Regents Of The University Of Michigan UEI GNJ7BBP73WE9
- Awarding agency
-
National Institute on Aging
National Institutes of Health, Department of Health and Human Services
- Obligated
- $44,039
Award facts
- Assistance listing
- 93.866 Aging Research
- Completion date 0% complete
- Place of performance
- Ann Arbor, MI 48109, USA
Award details come from USAspending.gov.
Description
- Abstract
- Alzheimer's disease (ad) is the leading cause of dementia, with women twice as likely to develop ad than men. This difference in prevalence highlights the importance of studying SEX specific, hormonal influences on the progression and development of the disease. The cumulative lifetime estrogen exposure (CLEE) hypothesis describes how increased exposures to estrogen, including longer reproductive span, pregnancy, hormone therapy, and hormonal contraceptives decrease risk for ad. Recent epidemiological studies have shown that oral contraceptive use can protect against cognitive decline and dementia even decades after use. This could be due in part to the ability of estrogen to regulate enzymatic cleavage and increase non- amyloidogenic processing of the amyloid precursor protein (APP). By reducing improper cleavage of APP via Β-secretase, one of the hallmark pathologies of ad (AΒ plaques), is mitigated before symptomology presents. Ad is associated with neuroimmune dysregulation as microglia become tonically activated in effort to clear debris and respond to surrounding neuronal death. This reactivity contributes to a toxic microenvironment and is a consequence of and contributor to further neuronal death and exacerbated ad pathology. Ovarian hormones have a complex modulatory effect on the neuroimmune system in which both estrogen and progesterone can modulate microglia reactivity and cytokine production. Thus, OC exposure may regulate neuroimmune reactivity via estrogen and progestin signaling, thereby protecting against ad progression. Based on preliminary data, we predict that OCS shift the neuroimmune system towards a protective state, decreasing microglia reactivity and inflammatory signaling. The main goal of this project is to identify how OC exposure acts as a protective exposure to ovarian hormones through mitigation of ad pathology progression and mediation of neuroimmune dysregulation. Our overall hypothesis is that OC exposure protects against ad progression via both increased cumulative lifetime estrogen exposure, and via regulation of neuroimmune dynamics. In this project, we will use a mouse model of OC exposure together with the APP/PS1 mouse model of alzheimer's disease with behavioral, pharmacological, and molecular tools to address this question. We will focus on interactions between OCS and APP cleavage mechanisms, and with neuroimmune cell signaling as mechanisms for protection against alzheimer's disease. This project will contribute to understanding how OCS, one of the most widely prescribed drugs in the world, acts to confer resilience against a disease which disproportionately affects women. Findings from this project will contribute to the greater understanding of hormonal influences on alzheimer's disease progression and development and overall women's health.
Quick answers
Who received award F31AG104361?
F31AG104361 was awarded to Regents Of The University Of Michigan by National Institute on Aging (National Institutes of Health) on February 26, 2027.
How much is award F31AG104361 worth?
$44,039 has been obligated on F31AG104361.
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