Apolipoprotein E, Smooth Muscle Cells and the Pathogenesis of Cerebral Amyloid Angiopathy: the Potential Role of Impaired Cerebrovascular Aβ Clearance

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Abstract
Cerebral amyloid angiopathy (CAA) is caused by the deposition of beta-amyloid (A beta) in Alzheimer disease brains. It also occurs isolated, representing a major cause for cerebral hemorrhage in the elderly. The E4 genotype of apolipoprotein E (ApoE) is a risk factor for CAA; however, the molecular mechanism underlying this genetic association is unknown. Various findings suggest that cerebrovascular A beta is derived from the soluble A beta contained in the cortical extracellular space or the cerebrospinal fluid (CSF) that communicates and surrounds small cortical or leptomeningeal vessels. CAA deposits are always intimately associated with smooth muscle cells (SMCs) or SMC-derived pericytes. As we have previously reported, SMCs internalize A beta in vitro via a lipoprotein pathway involving ApoE and the low-density lipoprotein receptor family. Internalized A beta is subsequently located to lysosomes, suggesting its intracellular degradation. We show that A beta is internalized via multiple pathways, because class A and class B scavenger receptors are also colocalized to A beta-containing endosomes in SMCs, and A beta uptake is inhibited by various scavenger receptor antagonists. It has been recently shown for different cell types that the cellular uptake of ApoE is more efficient for the ApoE3 isoform when compared to ApoE4 and that this isoform-specific difference depends on the presence of heparan sulfate proteoglycan (HSPG). HSPG is produced by SMCs and promotes A beta fibrillogenesis. We propose a pathogenetic model of CAA, in which the ApoE- and HSPG-mediated clearance of CSF-derived A beta peptides by SMCs protects the vascular extracellular matrix against critical A beta concentrations. Impairment of this pathway or its reduced efficiency in carriers of the ApoE4 genotype may increase the risk of developing CAA.