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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. Holtzman^1,2,3

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

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Received April 22, 2003; revised July 9, 2003; accepted July 10, 2003.

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