Human Apolipoprotein E4 Targeted Replacement Mice Show Increased Prevalence of Intracerebral Hemorrhage Associated with Vascular Amyloid Deposition

Abstract

Previous studies show that APOE *4 carriers are at increased risk for ischemic stroke and intracerebral hemorrhage (ICH). The APOE *4 gene is also linked to increased incidence of cerebral amyloid angiopathy. It has been suggested that apolipoprotein E4 expression leads to increased vascular amyloid deposition, which may explain the increased incidence of ICH in APOE *4 carriers. Here we show a significant increase in ICH in apoE4 targeted replacement mice compared with apoE3 mice. In all, 89% of the vessels in the apoE4 mice that showed evidence for hemorrhage contained fibrillar amyloid beta based on thioflavine-S staining. Aged apoE4 mice contained predominantly vascular amyloid deposits in the frontal cortex and hippocampus, but also showed evidence for parenchymal amyloid deposits. Most of the parenchymal amyloid appeared diffuse in nature; however, a small fraction was thioflavine-S positive, indicating presence of fibrillar amyloid. Electron microscopy further revealed evidence for fibrillar deposits in the vessel walls of apoE4 mice, but not apoE3 mice. The apoE4 targeted replacement mice do not harbor any mutation in the amyloid precursor protein gene and, therefore, are similar to the majority of humans susceptible to cerebral amyloid angiopathy and ICH, where the APOE genetic polymorphism is the only known genetic risk factor.