Multidisciplinary Phenotyping of a Novel Humanized LOAD Mouse Model

The risk of developing Alzheimer’s disease (AD) for individuals of African ancestry is twice as high as that for individuals of European ancestry. However, large genetic studies have been conducted almost exclusively in individuals of European ancestry. As part of the Cure Alzheimer’s Fund Alzheimer’s Genome ProjectÔ (AGP), Dr. Rudolph Tanzi’s group found a novel genetic variant of a gene called GGA3 associated with late-onset Alzheimer’s disease (LOAD) in African American families. Our previous studies demonstrated that GGA3 plays a critical role in the transport and regulation of BACE1, a key enzyme responsible for production of amyloid beta, the toxic protein that accumulates in the brain of AD patients. To study how this GGA3 rare variant leads to AD, we developed mice that express the human version of the GGA3 gene carrying the LOAD-linked variant. The aim of this study is to determine whether the presence of the GGA3 variant produces changes in the expression of genes and proteins like those observed in the brains of AD patients. Our studies may contribute to a better understanding of genetic risk factors in the African American population, which currently is understudied.