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Long-term Effects of Preeclampsia on Cerebrovascular Function and Cognitive Decline in Alzheimer's and Related Dementia

Description: Alzheimer's Disease (AD) and Alzheimer's Disease-Related Dementias (ADRD) are global health crises, with women disproportionately affected by higher disability-adjusted life years and mortality. The 2020 Lancet Commission on Dementia Prevention, Intervention, and Care suggests that up to 40% of dementia cases could be prevented or delayed by managing risk factors. One significant risk factor is preeclampsia (PE), a condition affecting 5-7% of pregnancies in the US, and up to 12% in Mississippi, defined by new-onset hypertension and more than one organ dysfunction during pregnancy. PE is characterized by inflammation and vascular endothelial dysfunction during pregnancy. Increasing evidence links PE to elevated levels of Aß, a hallmark of AD, blood-brain barrier (BBB) damage, and neuroinflammation. AD and ADRD are associated with cerebrovascular dysregulation and brain hypoperfusion. However, very little has been done to explore the mechanisms involved in PE-AD/ADRD cross-talk regarding long-term effects on cerebrovascular and cognitive function. This proposal aims to address this gap by investigating the long-term effects of PE on cerebrovascular and cognitive function using the APP/PS1 TgF344-AD rat model of AD and the Dahl/Salt-sensitive (SS) rat model of ADRD. We will use Reduced Uterine Perfusion Pressure (RUPP)-induced PE in AD and spontaneous PE in SS models to test the hypothesis that PE has a long-term negative impact on cerebral blood flow (CBF) autoregulation, neurovascular coupling (NVC), and contributes to neuroinflammation and neurodegeneration in AD and ADRD in later life. We will compare myogenic responses of cerebral arteries and arterioles, baseline CBF, functional hyperemia, and responses to endothelial nitric oxide and Kir2.1-mediated NVC in non-pregnant WT, AD and SS rats, normal pregnant (NP), and RUPP-induced PE AD (3 months postpartum) and pregnant SS (3 months postpartum) rats. We will evaluate BBB permeability, capillary density, tight junction protein expression, immune factor levels, and markers of astrogliosis, microgliosis, Aß burden, tau pathology, neurodegeneration, and cognitive performance. The findings from this proposal are expected to provide crucial insights into the long-term impacts of preeclampsia on cerebrovascular function and cognitive decline, potentially identifying new avenues for early intervention and prevention strategies for dementia.

Funder: American Heart Association

Amount: $153,700

Funding type: fellowship

Funder scheme: Postdoctoral Fellowship

Start date: 2025-01-01

End date: 2027-06-30

Investigators: Xing Fang, Xing Fang

Institution: University of Mississippi Medical Center

Topic: Pregnancy and preeclampsia studies

Subfield: Obstetrics and Gynecology

Field: Medicine

Domain: Health Sciences