Temporal Characterization of the Amyloidogenic APP/PS1dE9;hAPOE4 Mouse Model of Alzheimer’s Disease

Abstract Background The development of immunotherapies against Aβ is burdened by clinical adverse events (AEs) observed as amyloid‐related imaging abnormalities (ARIA) on magnetic resonance imaging scans. The vascular inflammatory AEs have been reported in AD clinical trials administrating certain anti‐Aβ plaque‐binding antibodies and are thought to represent cerebral microhemorrhages and vasogenic edema. ARIA incidence appears apolipoprotein (APOE) genotype‐dependent, wherein APOE E4 allele carriers are at higher risk when compared to non‐carriers. With hopes to robustly model patients most at risk for the vascular complications of anti‐Aβ immunotherapy, we selected a relatively new transgenic mouse model bearing the human APOE E4 gene. The model has not yet been extensively characterized at multiple age points. To assess the face validity of the mouse model, we are conducting a battery of histological and biochemical tests. Methods To evaluate age‐ and sex‐related pathological changes, we collected brain and blood plasma from euthanized male and female APP/PS1dE9;hAPOE4 (APP/E4) mice across 3 ages: 8‐, 12‐ and 16‐months. General‐ and pGlu3‐Aβ levels were quantified using enzyme‐linked immunoassays (ELISA). Prussian Blue hemosiderin staining was used to examine microhemorrhages. Results Immunoassays of brain homogenates exhibited significantly higher insoluble Aβ x‐40 , Aβ x‐42 and pGlu3Aβ levels in 16‐month‐old mice compared to 8‐ and 12‐month‐old mice. Moreover, the 16‐month‐old females demonstrated significantly higher levels of Aβ x‐40 and pGlu3Aβ than age‐matched males. Hemosiderin staining was observed in all 12‐ and 16‐month mice, however no significant differences in abundance was found between the 2 age points. Immunostainings for plaque deposition of various Aβ species, vascular amyloid, dystrophic neurites and gliosis are ongoing. Conclusions Age‐ and sex‐dependent increases in Aβ deposition were revealed in the APP/E4 mouse model. Preliminary evidence for microhemorrhage was observed. Subsequent analyses will better characterize the translational credibility of APP/E4 as a model for future nonclinical immunotherapies targeting Aβ. (1RF1AG058657‐CAL)