Neuroinflammatory Mechanisms of Vascular Cognitive Impairment

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ABSTRACT Aging-related dementia is a major public health concern that places an enormous emotional, physical, and financial stress on patients, their families and health-care systems. Clinical and epidemiological evidence suggests that the presence of vascular and metabolic risk factors, such as obesity, diabetes, dyslipidemia and hypertension, collectively known as the metabolic syndrome (MetS), during midlife increases the risk for and severity of dementia in late-life. The proposed studies will use the chronic high-fat diet (HFD) model of MetS in mice to investigate the mechanism and age-dependency of MetS-related cognitive dysfunction (MetSCD). Our observations made in postmortem human brain with a history of dementia and in brains of HFD-fed mice suggest that MetS increases the expression and activity of the enzyme soluble epoxide hydrolase (sEH) in brain microvascular endothelium, leading to reduced bioavailability of its substrate epoxyeicosatrienoates (EETs), which have anti-inflammatory properties. Reduced endothelial EETs predisposes to endothelial cell activation, peripheral immune cell infiltration into brain parenchyma, neuroinflammation and cognitive dysfunction. In support of a causal link between sEH upregulation, neuroinflammation and cognitive impairment, mice with endothelial overexpression of human sEH exhibit age-dependent neuroinflammation and cognitive deficit, while pharmacological inhibition of sEH protects against HFD-induced neuroinflammation and cognitive impairment. We will test the hypothesis that MetS contributes to late-life cognitive dysfunction via the infiltration of peripheral immune cells and progressive neuroinflammation. Aim 1 will use male and female wild-type (WT) mice and mice with endothelial-specific deletion of sEH, on standard (STD) or high-fat diet (HFD), to determine the role of endothelial sEH in MetSCD at 12 and 24 months of age. Aim 2 will use flow cytometry, immunohistochemistry (IHC) and single-cell RNAseq (scRNAseq) to determine if HFD induces an age- dependent neuroinflammatory response characterized by early infiltration of neutrophils and delayed infiltration of T and B lymphocytes. We will use immune cell reporter mice (Fgd5-CreERT2;Ai9) to confirm the peripheral origin of leukocytes, characterize the time course of immune cell invasion, and determine if endothelial-specific deletion of sEH prevents immune cell infiltration into the brain of mice on HFD. Aim 3 will determine if sEH inhibitors t-AUCB (brain-penetrant) and GSK2256294 (does not cross the blood-brain barrier, BBB) protect against neurocognitive impairment in mice on chronic HFD. We will also determine if there are sex differences in treatment effects. The proposed studies are highly translational, and will advance understanding of mechanisms and age-dependency MetSCD. The endothelial origin of age-dependent immune cell infiltration in MetSC is novel, and so is the use of scRNAseq and immune cell fate mapping using Fgd5-CreERT2; Ai9 mice.