Martine B. Grenon, Maria-Giusy Papavergi, Praveen Bathini, Maren K. Schroeder, Cynthia A. Lemere
Cynthia A. Lemere
The development of immunotherapies against Aβ is burdened by clinical adverse events (AEs) observed as amyloid-related imaging abnormalities (ARIA). Thought to represent vasogenic edema and cerebral microhemorrhages, vascular inflammatory AEs have been reported in clinical trials administrating certain anti-Aβ antibodies. Incidence of ARIA appears to be apolipoprotein (APOE) genotype-dependent, as APOE ε4 allele carriers hold higher risk in comparison to non-carriers. With hopes to model patients most at risk for the vascular AEs, we selected a relatively new transgenic mouse model that expresses human mutant amyloid and the human APOE ε4 gene. Using histological and biochemical analyses, we characterized APP/E3 and APP/E4 mice at three ages: 8, 12, and 16 months. Female and male mice were assayed for Aβ deposition, cerebral amyloid angiopathy, microhemorrhages, lipid composition, reactive astrocytes, microglial and inflammatory response, lysosomal dysfunction and neuritic dystrophy. At varying age points, APP/E4 mice showed elevation in measurements of Aβ deposition, APOE, reactive astrocytes, pro-inflammatory cytokines, lipid deposition, microglia response and proteasomal dysfunction in neurites in contrast to APP/E3s. Upcoming analyses of astrocyte and microglia morphology will better gauge the modulatory role of the E4 allele in the pathogenesis of AD.
Amyloid- plaques build up in the brain over many years in Alzheimer’s disease (AD) and may lead to other brain changes that result in dementia. Antibodies that bind and clear plaques are being examined as a therapy for AD, but some may induce transient vascular side-effects in the brain, seen by MRI scans as swelling or microhemorrhages. Patients that have the APOE E4 gene, one version of a cholesterol transport gene, are at a higher risk of these side effects. To test if new antibodies can avoid causing these side effects, a mouse breed “APP/E4” that develops amyloid- plaques was created with the human amyloid and APOE E4 genes. Here, we evaluated whether the APP/E4 mice accurately represent patients most at risk for these side effects and tried to understand how the APOE E4 gene increases risk. To investigate age- and sex-related changes, brain and blood samples were collected from euthanized male and female APP/E4 mice across 3 ages. Increases in plaque quantity and immune response signals were seen in mice with the APOE E4 gene.