Knockin mouse models of Alzheimer's Disease

Abstract Neuroinflammation has been increasingly recognized to play a critical role in Alzheimer’s disease (AD). The epoxy fatty acids (EpFAs) are derivatives of the arachidonic acid (ARA) metabolism with anti-inflammatory activities. However, their efficacy is limited due to the rapid hydrolysis by the soluble epoxide hydrolase (sEH). We found that sEH is predominantly expressed in astrocytes and its concentrations are elevated in postmortem brain tissue from AD patients and 5xFAD mice. The amount of sEH expressed in the 5xFAD moue brain is correlated with the reduction in EpFA concentrations. Using a specific small molecule sEH inhibitor, 1- trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), we reported that long-term treatment of TPPU to the 5xFAD mice restored EpFA levels and dampened neuroinflammation. This was associated with reduced β-amyloid pathology and improved cognitive function. Similar beneficial effects were obtained by genetic studies using Ephx2 (gene encoding sEH) knockout mice. These findings support sEH as a potential therapeutic target for AD. However, many questions remain to be addressed. In particular, how does the astrocytic sEH pathway communicate with microglia to regulate neuroinflammation? What is the role of brain vasculature known to subject to sEH regulation in this process? Whether and how sEH inhibition affect other ARA associated pathways and their lipid derivatives? We hypothesize that AD is associated with cell-type specific changes of the sEH and ARA metabolism in astrocytes, microglia and vascular endothelial cells, which mediate neuroinflammatory responses through cell-intrinsic mechanisms and cell-cell communications. To test this hypothesis, we will isolate microglia, astrocytes and vascular endothelial cells from the brains of aging and AD mouse models using our novel Concurrent Brain cell type Acquisition (CoBrA) methodology and perform cell-type specific gene expression and targeted lipidomics to evaluate how the ARA pathway and their lipid metabolites are changed in response to aging and beta-amyloid or neurofibrillary tangle pathologies. Further, we will determine whether and how sEH inhibition affords therapeutic benefit against AD pathologies and what are cell types and lipid species that mediate these effects. Overall, these studies will provide critical information concerning the mechanism-of- action and therapeutic targeting of sEH. It will also afford an in-depth understanding of the ARA metabolism and identify new targets that impact AD pathogenesis.