Effect of apolipoprotein E deficiency on small vessel pathology and cognitive impairment of a mouse model of chronic cerebral hypoperfusion

Abstract

Apolipoprotein E (APOE) plays a central role in controlling blood-brain barrier (BBB) permeability and maintaining cerebrovascular integrity. Subcortical vascular demen- tia (SVaD) is a subtype of vascular dementia and is associated with white matter damage, lacunar infarction and BBB breakdown. However, the relationship between APOE defi- ciency and factors associated with SVaD remains elusive. I recently established a mouse model of SVaD reflecting small vessel pathology and cognitive deficit. Ten to twelve weeks old APOE-deficient mice, or wild type C67BL/6J mice were subjected to chronic cerebral hypoperfusion with bilateral common carotid artery stenosis (BCAS) using microcoils or sham operation. Behavioral performance (locomotion, spatial working memory, and recognition memory), histopathological findings (white matter dam- age, microinfarctions, astrogliosis, and hippocampal neuronal damage), and cerebral micro- circulation (microvascular density and BBB integrity) were investigated. APOE deficiency in BCAS operated mice shows white matter damage, astrogliosis, hippocampal neuronal loss, BBB breakdown, and impaired locomotion, spatial working memory, and recognition memory. In particular, hippocampal neuronal loss, decreased lo- comotor activitiy, and impaired recognition memory were only observed in the $ApoE^{-/-} BCAS$ mice, but not in either $ApoE^{-/-}$ or BCAS operation alone. When combined with chronic cerebral hypoperfusion, APOE deficiency enhances cognitive decline, neuronal damage, and small vessel pathology in mice. The current mouse model reflects the phenotypes of human SVaD, including small vessel pathology with hip- pocampal neuronal damage and cognitive impairment thus can be a plausible model for studying SVaD pathophysiology and drug study for it.