APOE4 PROMOTES THE DYSFUNCTION OF BRAIN BLOOD VESSELS, GLIAL NEUROINFLAMMATION, AND ACCUMULATION OF SENILE PLAQUES IN THE PREFRONTAL CORTEX OF APPSWE/PS1DE9 ALZHEIMER’S DISEASE MODEL MICE

Abstract

A major genetic risk factor for Alzheimer's Disease (AD) is the ɛ4 isoform of apolipoprotein E (ApoE4). APOE4 is one of the three common forms of the APOE gene; however, it is still unclear how APOE4gene increases the risk of AD. The purpose of this study is to examine the pathogenesis of human ApoE4 molecules in the brain of AD model mouse. We used ApoE4/E4 knock-in and ApoE3/E3 knock-in mice. To intercalate human APOE4 or APOE3 gene into AD model mouse, we used an APPswe/PS1dE9 AD model mice. We generated ApoE4/E4 AD mice, which possessed the single copy of APPswe/PS1dE9 transgene gene. As controls, we also generated ApoE3/E3 AD. At 9 months of age, the levels of senile plaques in the hippocampus and the prefrontal cortex were evaluated by X34-histochemical staining. To evaluate the extent of the glial inflammatory reactions, we performed immunostaining for detecting the astrocytes and the microglia, respectively. To evaluate the blood vessels dysfunction, we used tomato lectin and anti-PDGFR-β to visualize the vascular endothelial cells and the capillary pericytes, respectively. Using these methods, the cover ratio of pericyte in lectin positive endothelial cells was evaluated in confocal microscopic images. We observed accumulation of senile plaques in the cortex of ApoE4/E4 AD mice, but not in ApoE3/E3 AD mice (student's t-test, p<0.005). We compared the coverage of pericytes on the brain capillary vessel at the cortex and observed the significant reduction (p<0.01) in ApoE4/E4 AD mice, as compared to ApoE3/E3 AD mice. We also detected the significant glial neuroinflammation in ApoE4/E4 AD mice compared with ApoE3/E3 AD mice (p<0.05). These data may indicate that the dysfunction of brain blood vessel as well as the glial neuroinflammatory reactions cause the accumulation of senile plaques in the prefrontal cortex of ApoE4/E4 AD mice. The formation of senile plaques, the dysfunction of the blood vessel, and the inflammation were severed in ApoE4/E4 AD mice as compared to ApoE3/E3 AD mice. These data suggested a difference of Aβ clearance was observed in ApoE4/E4 AD mice by the dysfunction of their brain blood vessels.