Apolipoprotein E Transgenic Mouse Model of Cerebral Amyloid Angiopathy

Abstract

76 Background: Cerebral amyloid angiopathy (CAA) is the second most common etiology for non-traumatic intracerebral hemorrhage (ICH). There is a significantly increased frequency of the apolipoprotein E (apoE) e4 and e2 alleles in patients with CAA and CAA-related ICH. This suggests a role for apoE in the pathogenesis of CAA and ICH. We have developed a unique transgenic mouse model using the human apoE gene to study the molecular mechanisms underlying CAA. Methods: The transgenic mouse model was created by gene targeting, which results in the expression of each human apoE isoform at physiologic levels in a correct spatial and temporal pattern. These mice do not contain any mutations in the amyloid precursor protein or cystatin C gene. Mice of all apoE genotypes were bred, and were matched for age and sex. Brains from aged mice were analyzed for gross ICH. Brain sections were stained with anti-mouse A-beta antibody (4G8) to detect vascular amyloid. Sections were also stained for blood using hematoxylin and eosin (H&E), and a Prussian Blue stain was used to detect iron and hemosiderin deposition. A thioflavin-S stain was used to determine if the vascular amyloid was fibrillar. Results: Brains from sacrificed aged (mean age=80 weeks) apoE transgenic mice showed positive staining for CAA in predominantly neocortical vessels. The apoE e2/e2 mice had the highest occurrence of CAA (70%, 7 of 10), followed by the e4/e4 mice (40%, 4 of 10). Only 10% (1 of 10) of the e3/e3 mice had CAA. Two aged mice homozygous for apoE e4 had gross ICH at post-mortem inspection. Brain sections from these mice demonstrated red blood cell infiltration and iron/hemosiderin deposition in the brain parenchyma when examined by light microscopy. Conclusions: This human apoE transgenic mouse model provides a genetically well defined and environmentally controlled animal model for the study of CAA that closely resembles the condition found in humans. This model may be useful for the study of therapies for the prevention and treatment of CAA.