Martine B. Grenon, Praveen Bathini, Maria-Giusy Papavergi, Maren K. Schroeder, Cynthia A. Lemere
Cynthia A. Lemere
Research Category: Neurosciences
The development of immunotherapies against Aβ is burdened by clinical adverse events (AEs) observed as amyloid-related imaging abnormalities (ARIA). Thought to represent cerebral microhemorrhages and vasogenic edema, 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 E4 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 bearing the human APOE E4 gene.
We conducted a battery of histological and biochemical tests to assess the face validity of the mouse model. To evaluate age- and sex-related pathological changes, brain and blood plasma was collected from euthanized male and female APP/PS1;hAPOE4 (APP/E4) mice across 3 ages: 8-, 12- and 16-months. Immunoassays of brain homogenates and staining of hippocampal sections revealed age-dependent increase in Aβ deposition. Hemosiderin staining was observed in all 12- and 16-month mice, however no significant effect of genotype or age was found on microhemorrhage abundance. Upcoming analyses of dystrophic neurites and gliosis will better characterize the translational credibility of APP/E4 as a model for future nonclinical immunotherapies targeting Aβ.
Amyloid-β 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 many induce transient vascular side-effects in the brain, seen by MRI scans, 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-β plaques was created with the human APOE E4 gene. Here, we evaluated whether the APP/E4 mice accurately represent patients most at risk for these side effects. To investigate age- and sex-related changes, brain and blood samples were collected from euthanized male and female APP/E4 mice across 3 ages. Plaque load was higher in females than males and increased with age. Microhemorrhages were seen in older mice but did not differ between males and females.