P2‐131: Novel Apoe4.trem2*r47h Mouse Model: a Better Tool for Late‐onset Alzheimer's Disease
Year: 2019
Type: article
Abstract: Current animal models do not fully recapitulate late-onset Alzheimer's Disease (LOAD), thus are not ideal for therapy development. To address this, the Model Organism Development and Evaluation for Late-onset AD consortium (MODEL-AD) has created a novel LOAD mouse carrying two common risk alleles. Characterization of this model at young and advanced ages will indicate more appropriate disease mechanisms useful in the treatment of LOAD. Humanized APOEe4 and the Trem2*R47H mutation, two prominent genetic risk factors for LOAD, were inserted into the genome of C57BL/6J mice to create the B6.APOEe4.Trem2*R47H (B6J.hAT) model. Cohorts of B6J.hAT (with controls) were established at JAX and IU and aged to 2, 6, 12, and 24 months. At JAX, in vivo behavior and wellness assays measured activity, frailty, grip strength, coordination, and cognitive ability. At IU, MRI and PET studies using [18F]-FDG and [64Cu]-PTSM were completed. Post-mortem analyses at both sites included blood chemistry, brain immunohistochemistry, transcriptomics and proteomics. By 12 months, female B6J.hAT mice displayed reduced frailty index scores, a measure of aging and vulnerability, suggesting a protective phenotype. However, no differences were observed in cognition, activity, or locomotion. B6J.hAT and B6.APOEe4 mice showed decreased levels of total cholesterol, LDL, and HDL at multiple time points - an effect of the APOEe4 allele that has been reported previously. PET data showed some changes in glucose uptake over time in B6J.hAT mice, but MRI showed no gross abnormalities of the brain and post-mortem brain weight was unchanged. Transcriptomics revealed age-related changes in B6J.hAT brain samples compared to controls. Differentially expressed genes were enriched in multiple AD-related pathways including immune response, splicesome, and osteoclast differentiation. We also observed a novel splicing event in mice expressing the Trem2*R47H variant. Phenotyping of the 24-month cohort is in progress as is a pilot proteomics experiment. The MODEL-AD consortium has established a new mouse strain to study the effects of two strong risk factors for LOAD. This model is also serving as a backbone strain for the further addition of LOAD risk alleles to more closely align phenotypes in the mouse to outcomes observed in human AD.
Source: Alzheimer s & Dementia
Language: English
Subfield: Physiology (medical)
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2981209358