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From the Experimental Genetics Group,*
Center
for Human Genetics, Flemish Institute for Biotechnology, the Center for
Transgene Technology and Gene Therapy,
Center
for Molecular and Vascular Biology, and Genetic
Epidemiology,§
K.U.Leuven, Leuven, Belgium; the
Janssen Research Foundation,
Beerse, Belgium;
Innogenetics,¶
Gent, Belgium; Institut de
Pharmacology Moléculaire et Cellulaire/CNRS,||
Valbonne, France; and the Department of
Pathology,**
University Hospitals Leuven,
Leuven, Belgium
Deposition of amyloid ß-peptide (Aß) in cerebral vessel walls
(cerebral amyloid angiopathy, CAA) is very frequent in
Alzheimer’s disease and occurs also as a sporadic disorder.
Here, we describe significant CAA in addition to amyloid
plaques, in aging APP/Ld transgenic mice overexpressing the
London mutant of human amyloid precursor protein (APP) exclusively in
neurons. The number of amyloid-bearing vessels increased with
age, from 
10 to >50 per coronal brain section in APP/Ld
transgenic mice, aged 13 to 24 months. Vascular amyloid was
preferentially deposited in arterioles and ranged from small focal to
large circumferential depositions. Ultrastructural analysis allowed us
to identify specific features contributing to weakening of the vessel
wall and aneurysm formation, ie, disruption of the
external elastic lamina, thinning of the internal elastic
lamina, interruption of the smooth muscle layer, and
loss of smooth muscle cells. Biochemically, the much lower
Aß42:Aß40 ratio evident in vascular relative to plaque
amyloid, demonstrated that in blood vessel walls Aß40 was the
more abundant amyloid peptide. The exclusive neuronal origin of
transgenic APP, the high levels of Aß in cerebrospinal fluid
compared to plasma, and the specific neuroanatomical
localization of vascular amyloid strongly suggest specific drainage
pathways, rather than local production or blood uptake of Aß
as the primary mechanism underlying CAA. The demonstration in APP/Ld
mice of rare vascular amyloid deposits that immunostained only for
Aß42, suggests that, similar to senile plaque
formation, Aß42 may be the first amyloid to be deposited in
the vessel walls and that it entraps the more soluble Aß40. Its
ability to diffuse for larger distances along perivascular drainage
pathways would also explain the abundance of Aß40 in vascular
amyloid. Consistent with this hypothesis, incorporation of
mutant presenilin-1 in APP/Ld mice, which resulted in
selectively higher levels of Aß42, caused an increase in CAA
and senile plaques. This mouse model will be useful in further
elucidating the pathogenesis of CAA and Alzheimer’s
disease, and will allow testing of diagnostic and
therapeutic strategies.
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