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The Journal of Neuroscience, March 16, 2005, 25(11):2803-2810; doi:10.1523/JNEUROSCI.5170-04.2005

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Neurobiology of Disease
Human Apolipoprotein E4 Alters the Amyloid- 40:42 Ratio and Promotes the Formation of Cerebral Amyloid Angiopathy in an Amyloid Precursor Protein Transgenic Model

John D. Fryer,¹ Kelly Simmons,¹ Maia Parsadanian,¹ Kelly R. Bales,⁴ Steven M. Paul,^4,5 Patrick M. Sullivan,⁶ and David M. Holtzman^1,2,3

Departments of ¹Neurology and ²Molecular Biology and Pharmacology and ³Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri 63110, ⁴Neuroscience Discovery Research, Eli Lilly and Company, Lilly Research Laboratories, Indianapolis, Indiana 46285, ⁵Departments of Pharmacology, Toxicology, and Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana 46285, and ⁶Bryan Alzheimer's Disease Research Center and Division of Neurology, Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710

Alzheimer's disease (AD) is characterized by the aggregation and deposition of the normally soluble amyloid- (A) peptide in the extracellular spaces of the brain as parenchymal plaques and in the walls of cerebral vessels as cerebral amyloid angiopathy (CAA). CAA is a common cause of brain hemorrhage and is found in most patients with AD. As in AD, the 4 allele of the apolipoprotein E (apoE) gene (APOE) is a risk factor for CAA. To determine the effect of human apoE on CAA in vivo, we bred human APOE3 and APOE4 "knock-in" mice to a transgenic mouse model (Tg2576) that develops amyloid plaques as well as CAA. The expression of both human apoE isoforms resulted in a delay in A deposition of several months relative to murine apoE. Tg2576 mice expressing the more fibrillogenic murine apoE develop parenchymal amyloid plaques and CAA by 9 months of age. At 15 months of age, the expression of human apoE4 led to substantial CAA with very few parenchymal plaques, whereas the expression of human apoE3 resulted in almost no CAA or parenchymal plaques. Additionally, young apoE4-expressing mice had an elevated ratio of A 40:42 in brain extracellular pools and a lower 40:42 ratio in CSF, suggesting that apoE4 results in altered clearance and transport of A species within different brain compartments. These findings demonstrate that, once A fibrillogenesis occurs, apoE4 favors the formation of CAA over parenchymal plaques and suggest that molecules or treatments that increase the ratio of A 40:42 may favor the formation of CAA versus parenchymal plaques.

Key words: Alzheimer's disease; apolipoprotein E; cerebral amyloid angiopathy; amyloid-; ratio; transgenic models

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Received Dec 18, 2004; revised January 25, 2005; accepted January 28, 2005.

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