National Institute on Aging 2RF1AG058273-02A1

Neuroinflammatory Mechanisms of Vascular Cognitive Impairment

This award funds research on how metabolic syndrome contributes to late-life cognitive dysfunction through neuroinflammation, using mouse models and advanced molecular techniques to explore mechanisms and potential therapies.

Description

Aging-related dementia is a major public health concern that places an enormous emotional, physical, and financial stress on patients, their families, and healthcare systems. Clinical and epidemiological evidence suggests that vascular and metabolic risk factors, such as obesity, diabetes, dyslipidemia, and hypertension, collectively known as metabolic syndrome (MetS), during midlife increase the risk and severity of dementia in late life. The proposed studies will utilize a chronic high-fat diet (HFD) model of MetS in mice to investigate the mechanisms and age-dependency of MetS-related cognitive dysfunction (MetSCD). Observations in postmortem human brains with a history of dementia and in brains of HFD-fed mice suggest that MetS increases the expression and activity of soluble epoxide hydrolase (sEH) in brain microvascular endothelium, leading to reduced bioavailability of epoxyeicosatrienoates (EETs), which have anti-inflammatory properties. Reduced endothelial EETs predispose to endothelial cell activation, peripheral immune cell infiltration into brain parenchyma, neuroinflammation, and cognitive dysfunction. Mice with endothelial overexpression of human sEH exhibit age-dependent neuroinflammation and cognitive deficits, while pharmacological inhibition of sEH protects against HFD-induced neuroinflammation and cognitive impairment. The study aims to test the hypothesis that MetS contributes to late-life cognitive dysfunction via infiltration of peripheral immune cells and neuroinflammation. It involves using wild-type and endothelial-specific sEH knockout mice on standard or high-fat diets at 12 and 24 months of age, employing flow cytometry, immunohistochemistry, and single-cell RNA sequencing to analyze immune responses, and testing sEH inhibitors for neuroprotective effects.

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