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Cerebrovascular
Smooth Muscle Cells Internalize Alzheimer Amyloid Beta Protein via a Lipoprotein
Pathway: Implications for Cerebral Amyloid Angiopathy |
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Britta Urmoneit,
Ingrid Prikulis, GAdunther Wihl, Donatella D'Urso, Rainer Frank, JAdorg
Heeren, Ulrike Beisiegel, and Reinhard Prior |
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Departments
of Neurology (BU, IP, RP) and Molecular Neurobiology (DD), University of
DAdusseldorf, DAdusseldorf; Medical Clinic, University of Hamburg (JH, UB),
Hamburg; and Center for Molecular Biology (RF), University of Heidelberg,
Heidelberg, Germany |
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Cerebral amyloid angiopathy
(CAA) is caused by the cerebrovascular deposition of Alzheimer amyloid beta
protein (A beta) and shows an increased incidence in carriers of the apolipoprotein
E (APOE) epsilon 4 genotype. 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 lysosomal
vesicles. The accumulation of intracellular A beta was enhanced by chloroquine
and blocked by cycloheximide and brefeldin A and pretreatment with trypsin,
suggesting that the internalization of A beta occurs by receptor-mediated
endocytosis. The internalization of A beta was also inhibited by lipoprotein-deficient
serum or by incubation with the 39-kd receptor-associated protein, indicating
that A beta is internalized via a receptor of the low-density lipoprotein
receptor family. A lipoprotein pathway was confirmed by colocalization of
cell surface-bound or internalized A beta with APOE and low-density lipoprotein
receptor-related protein. We propose a pathogenetic model of CAA, in which
A beta -APOE-complexes contained within the cerebrospinal fluid or the extracellular
fluid of the brain are internalized and accumulated in cerebrovascular smooth
muscle cells. Such a model could explain the preferential localization of
CAA to the outer and middle layers of cortical and leptomeningeal arterioles,
while indicating a mechanism by which the APOE genotype might determine
the risk of CAA. |
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