Neuroinflammatory Mechanisms of Vascular Cognitive Impairment

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.

Grant Number: 2RF1AG058273-02A1
NIH Institute/Center: NIH
Principal Investigator: Nabil Alkayed