Deficiency in EP4 Receptor-Associated Protein Ameliorates Abnormal Anxiety-Like Behavior and Brain Inflammation in a Mouse Model of Alzheimer Disease

Abstract

Microglia are thought to play key roles in the progression of Alzheimer disease (AD). Overactivated microglia produce proinflammatory cytokines, such as tumor necrosis factor-α, which appear to contribute to disease progression. Previously, we reported that prostaglandin E₂ type 4 receptor-associated protein (EPRAP) promotes microglial activation. We crossed human amyloid precursor protein transgenic mice from strain J20^+/- onto an EPRAP-deficient background to determine the role of EPRAP in AD. Behavioral tests were performed in 5-month-old male J20^+/-EPRAP^+/+ and J20^+/-EPRAP^-/- mice. EPRAP deficiency reversed the reduced anxiety of J20^+/- mice but did not affect hyperactivity. No differences in spatial memory were observed between J20^+/-EPRAP^+/+ and J20^+/-EPRAP^-/- mice. In comparison with J20^+/-EPRAP^+/+, J20^+/-EPRAP^-/- mice exhibited less microglial accumulation and reductions in the Cd68 and tumor necrosis factor-α mRNAs in the prefrontal cortex and hippocampus. No significant differences were found between the two types of mice in the amount of amyloid-β 40 or 42 in the cortex and hippocampus. J20^+/-EPRAP^-/- mice reversed the reduced anxiety-like behavior and had reduced microglial activation compared with J20^+/-EPRAP^+/+ mice. Further research is required to identify the role of EPRAP in AD, but our results indicate that EPRAP may be related to behavioral and psychological symptoms of dementia and inflammation in patients with AD.