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The Journal of Neuroscience, August 27, 2003, 23(21):7889-7896
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Apolipoprotein E Markedly Facilitates Age-Dependent Cerebral Amyloid Angiopathy and Spontaneous Hemorrhage in Amyloid Precursor Protein Transgenic Mice
John D. Fryer,1
Jennie W. Taylor,1
Ronald B. DeMattos,4
Kelly R. Bales,4
Steven M. Paul,4,5
Maia Parsadanian,1 and
David M. Holtzman1,2,3
Departments of 1Neurology and
2Molecular Biology and Pharmacology and the
3Center for the Study of Nervous System Injury,
Washington University School of Medicine, St. Louis, Missouri 63110,
4Neuroscience Discovery Research, Eli Lilly and
Company, Lilly Research Laboratories, Indianapolis, Indiana 46285, and
5Departments of Pharmacology, Toxicology, and
Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana
46285
Cerebral amyloid angiopathy (CAA) is a common cause of brain hemorrhage in
the elderly. It is found in the majority of patients with Alzheimer's disease
(AD). The most common form of CAA is characterized by the deposition of the
amyloid- (A) peptide in the walls of cerebral vessels, and this
deposition can lead to hemorrhage and infarction. As in AD, the  4 allele
of apolipoprotein E (APOE) is a risk factor for CAA. To determine the
effect of apoE on CAA and associated hemorrhage in vivo, we used two
amyloid precursor protein (APP) transgenic mouse models that develop
age-dependent A deposition: PDAPP and APPsw mice. We found that both
models developed an age-dependent increase in CAA and associated
microhemorrhage, with the APPsw model having an earlier and more severe
phenotype; however, when APPsw and PDAPP mice were bred onto an
Apoe-/- background, no CAA was detected through 24 months of age, and
there was little to no evidence of microhemorrhage. Biochemical analysis of
isolated cerebral vessels from both PDAPP and APPsw mice with CAA revealed
that, as in human CAA, the ratio of A 40:42 was elevated relative to
brain parenchyma. In contrast, the ratio of A 40:42 from cerebral
vessels isolated from old PDAPP, Apoe-/- mice was extremely low.
These findings demonstrate that murine apoE markedly promotes the formation of
CAA and associated vessel damage and that the effect of apoE combined with the
level of A40 or the ratio of A 40:42 facilitates this
process.
Key words: Alzheimer's disease; apolipoprotein E; cerebral amyloid angiopathy; amyloid ; ratio; hemorrhage; transgenic models
Received April 22, 2003;
revised July 9, 2003;
accepted July 10, 2003.
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