CEREBROVASCULAR SMOOTH-MUSCLE CELLS INTERNALIZE ALZHEIMER AMYLOID-BETA PROTEIN VIA A LIPOPROTEIN PATHWAY - IMPLICATIONS FOR CEREBRAL AMYLOID ANGIOPATHY

Cerebral amyloid angiopathy (CAA) is caused by the cerebrovascular dep osition of Alzheimer amyloid beta protein (A beta) and shows an increa sed incidence in carriers of the apolipoprotein E (APOE) epsilon 4 gen otype. To study the pathogenesis of CAA, primary cultures of human and canine smooth muscle cells from leptomeningeal vessels were incubated with fluorescein- and biotin-conjugated amyloid beta-protein. In the presence of human serum or cerebrospinal fluid, A beta 1-40 and A beta 1-42 were rapidly internalized and appeared within endosomal and lyso somal vesicles. The accumulation of intracellular A beta was enhanced by chloroquine and blocked by cycloheximide and brefeldin A and pretre atment with trypsin, suggesting that the internalization of A beta occ urs by receptor-mediated endocytosis. The internalization of A beta wa s also inhibited by lipoprotein-deficient serum or by incubation with the 39-kd receptor-associated protein, indicating that AP is internali zed via a receptor of the low-density lipoprotein receptor family. A l ipoprotein pathway was confirmed by colocalization of cell surface-bou nd or internalized A beta with APOE and low-density lipoprotein recept or-related protein. We propose a pathogenetic model of CAA, in which A beta-APOE-complexes contained within the cerebrospinal fluid or the e xtracellular fluid of the brain are internalized and accumulated in ce rebrovascular smooth muscle cells. Such a model could explain the pref erential localization of CAA to the outer and middle layers of cortica l and leptomeningeal arterioles, while indicating a mechanism by which the APOE genotype might determine the risk of CAA.