Abstract 119: Apoe-ɛ4 Is Associated With Cerebrovascular Insufficiency, Increased Susceptibility to White Matter Injury and Cognitive Dysfunction
ApoE-ɛ4 (apoE4) is a risk factor for white matter ischemic lesions (Neurology 81:292, 2013) and Alzheimer’s disease (Neuron 63:287, 2009). However, the underlying mechanisms remain to be defined. We tested the hypothesis that the apoE4 allele is associated with alterations in the regulation of the cerebral circulation and increased white matter susceptibility to ischemic injury. To this end, we used human ApoE targeted replacement mice (Sullivan et al., JBC, 272:17972, 1997) in which cerebral blood flow (CBF) was measured by laser-Doppler flowmetry in the somatosensory cortex under anesthesia (n=5/group; age 4 mo.). In apoE4 mice, the increase in CBF produced by whisker stimulation (WS) or by topical application of the endothelium-dependent vasodilator acetylcholine (ACh) was attenuated (WS, -48%; ACh, -39%; p<0.05; mean±SE). Next, we asked if this neurovascular dysfunction increases the propensity of apoE4 mice to develop white matter ischemic lesions. White matter hypoperfusion was induced in the corpus callosum by bilateral carotid artery stenosis (BCAS) with microcoils for 4 weeks. BCAS led to more severe white matter injury in apoE4 than in apoE3 mice. Thus, BCAS reduced myelin density more in apoE4 (10±1 relative fluorescence units) than in apoE3 mice (15±1), a reduction of 33% (p<0.05). Furthermore, the axonal nodal structure, assessed by the NaV1.6/caspr index, was disrupted in apoE4 mice (normal index 0.5; BCAS apoE3: 0.58±0.13; BCAS apoE4: 1.05±0.13; p<0.05 from apoE3). BCAS induced impairments in spatial memory in the Y-maze test (arm alternation rate), an effect worse in apoE4 (43±3%) than apoE3 mice (52±3) (p<0.05). These findings suggest that the apoE4 allele is associated with cerebrovascular dysfunction, which leads to more severe white matter damage and cognitive deficits following exposure to chronic cerebral hypoperfusion. Cerebrovascular alterations in apoE4 carriers may play a role in the cognitive impairment associated with vascular risk factors and in the ischemic pathology associated with Alzheimer's disease.
Author Disclosures: K. Koizumi: None. L. Park: None. L. Zhao: None. W. Luo: None. S.M. Paul: None. C. Iadecola: None.
This research has received full or partial funding support from the American Heart Association, National Center.
- © 2015 by American Heart Association, Inc.