Department of Neurology, University of Duesseldorf, Moorenstrasse 5, D-40225 Duesseldorf, Germany
Cerebral amyloid angiopathy (CAA) is caused by the deposition
of ß-amyloid (Aß) 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 Aß is derived from the
soluble Aß 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 Aß
in vitro via a lipoprotein pathway
involving ApoE and the low-density lipoprotein receptor family.
Internalized Aß is subsequently located to lysosomes,
suggesting its intracellular degradation. We show that Aß
is internalized via multiple pathways, because class A and class
B scavenger receptors are also colocalized to Aß-containing
endosomes in SMCs, and Aß 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 Aß fibrillogenesis. We propose a pathogenetic
model of CAA, in which the ApoE- and HSPG-mediated clearance
of CSF-derived Aß peptides by SMCs protects the vascular
extracellular matrix against critical Aß concentrations.
Impairment of this pathway or its reduced efficiency in carriers
of the ApoE4 genotype may increase the risk of developing CAA.
