The role of APOE in cerebrovascular dysfunction

Abstract

The ε4 allele of the apolipoprotein E gene (APOE4) is associated with cognitive decline during aging, is the greatest genetic risk factor for Alzheimer's disease and has links to other neurodegenerative conditions that affect cognition. Increasing evidence indicates that APOE genotypes differentially modulate the function of the cerebrovasculature (CV), with apoE and its receptors expressed by different cell types at the CV interface (astrocytes, pericytes, smooth muscle cells, brain endothelial cells). However, research on the role of apoE in CV dysfunction has not advanced as quickly as other apoE-modulated pathways. This review will assess what aspects of the CV are modulated by APOE genotypes during aging and under disease states, discuss potential mechanisms, and summarize the therapeutic significance of the topic. We propose that APOE4 induces CV dysfunction through direct signaling at the CV, and indirectly via modulation of peripheral and central pathways. Further, that APOE4 predisposes the CV to damage by, and exacerbates the effects of, additional risk factors (such as sex, hypertension, and diabetes). ApoE4-induced detrimental CV changes include reduced cerebral blood flow (CBF), modified neuron-CBF coupling, increased blood-brain barrier leakiness, cerebral amyloid angiopathy, hemorrhages and disrupted transport of nutrients and toxins. The apoE4-induced detrimental changes may be linked to pericyte migration/activation, astrocyte activation, smooth muscle cell damage, basement membrane degradation and alterations in brain endothelial cells.

Keywords: Aging; Alzheimer’s disease; Apolipoprotein E; Blood–brain barrier; Cerebrovascular dysfunction.

Fig.1. Expression of APOE and apoE receptors in the CNS

(a) Arterioles. (b) Capillaries that define the blood-barrier (BBB).

Fig.2. CV deficits with APOE4 and Aβ in EFAD mice

CD31 (green) and Aβ (red, using the MOAB-2 antibody) staining in 8 month old male mice that express APOE4 and overexpress human Aβ (EFAD mice described in [140]). (a) 10× magnification, scale bar = 100µm (b–e) 63× magnification, scale bar = 20µm.

Fig.3. Pathways of APOE modulated neurovascular dysfunction

APOE4 imparts negative effects on a multitude of peripheral and CNS pathways that may contribute to cerebrovascular dysfunction and lead to cognitive impairment. Brain endothelial cells may act as the primary effector interface for these pathways.

Fig.4. Therapeutic targets for APOE modulated cerebrovascular dysfunction