Abstract 101: ApoE4 Disrupts Cerebrovascular Microcirculation and Undermines White Matter Integrity and Cognitive Function

Abstract

Background: Small vessel disease leading to subcortical white matter lesions (WML) is the major cause of vascular cognitive impairment. The apolipoprotein E4 (ApoE4) allele, a well-known risk factor for Alzheimer’s disease, is also a risk factor for WML, but the mechanisms of the effect remain unclear. We set out to determine whether the ApoE4 genotype disrupts the cerebral microcirculation and promotes WML and cognitive impairment. Methods: We studied male ApoE4 targeted replacement mice (ApoE4-TR; age 3-4 months). ApoE3 (ApoE3-TR) were used as controls. Cerebral blood flow (CBF) was assessed by ASL-MRI; the CBF increase induced by whisker stimulation (WS) or the endothelium-dependent agent acetylcholine (ACh) was assessed in cranial window preparations by laser-Doppler flowmetry. The corpus callosum (CC) microcirculation was examined by three-photon microscopy (3PM). Bilateral carotid artery stenosis (BCAS) was induced with 0.18 mm microcoils. WML and cognition were tested 4 weeks after BCAS. Results: In ApoE4-TR mice resting cortical CBF was attenuated compared to ApoE3-TR (-13%), as well the increase in CBF produced by WS (-47±3%) or ACh (-38±3%; p<0.05; n=5/group). In the CC, red blood cell (RBC) speed was slower in ApoE4-TR (1.6±0.1) than in ApoE3 mice (1.9±0.1 mm/s; p<0.05; n=5/group). Following 4 weeks of BCAS, cortical CBF was reduced more in ApoE4-TR (-35±4%) than in ApoE3-TR mice (-23±2%; p<0.05; n=8/group). Similarly, in the CC RBC speed was reduced more in ApoE4-TR (-33±3%) than in ApoE3-TR mice (-23±3%; p<0.05; n=5/group). In ApoE4-TR mice BCAS resulted in more marked CC WML (SMI312/MBP ratio, 48%) and cognitive dysfunction (novel object recognition: 18%; Y-maze arm alternation: 14%) than in ApoE3-TR mice (p<0.05; n=8/group). Conclusions: The findings unveil a previously unrecognized ApoE4-dependent failure of critical neurovascular regulatory mechanisms, sufficient to promote white matter damage in the setting of cerebral hypoperfusion. Such alterations may be responsible for the increased susceptibility to hypoxic-ischemic lesions in the subcortical white matter of individuals carrying the ApoE4 allele.