Apolipoprotein E markedly facilitates age-dependent cerebral amyloid angiopathy and spontaneous hemorrhage in amyloid precursor protein transgenic mice.
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-beta (Abeta) peptide in the walls of cerebral vessels, and this deposition can lead to hemorrhage and infarction. As in AD, the epsilon4 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 Abeta 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 Abeta 40:42 was elevated relative to brain parenchyma. In contrast, the ratio of Abeta 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 Abeta40 or the ratio of Abeta 40:42 facilitates this process.
Fryer
John D
JD
Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Taylor
Jennie W
JW
DeMattos
Ronald B
RB
Bales
Kelly R
KR
Paul
Steven M
SM
Parsadanian
Maia
M
Holtzman
David M
DM
D000367:Age Factors; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000502:physiology*; D016657:Cerebral Amyloid Angiopathy / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D002540:Cerebral Cortex / Q000098:blood supply / Q000378:metabolism; D002543:Cerebral Hemorrhage / Q000209:etiology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000378:metabolism
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D001057:Apolipoproteins E; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)