Apolipoprotein E markedly facilitates age-dependent cerebral amyloid angiopathy and spontaneous hemorrhage in amyloid precursor protein transgenic mice

John D. Fryer, Jennie W. Taylor, Ronald B. DeMattos, Kelly R. Bales, Steven M. Paul, Maia Parsadanian, David M. Holtzman

Research output: Contribution to journalArticle

123 Scopus citations

Abstract

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-β (Aβ) peptide in the walls of cerebral vessels, and this deposition can lead to hemorrhage and infarction. As in AD, the ε4 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 Aβ 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 Aβ 40:42 was elevated relative to brain parenchyma. In contrast, the ratio of Aβ 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 Aβ40 or the ratio of Aβ 40:42 facilitates this process.

Original languageEnglish
Pages (from-to)7889-7896
Number of pages8
JournalJournal of Neuroscience
Volume23
Issue number21
DOIs
StatePublished - Aug 27 2003

Keywords

  • Alzheimer's disease
  • Amyloid β
  • Apolipoprotein E
  • Cerebral amyloid angiopathy
  • Hemorrhage
  • Ratio
  • Transgenic models

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