ABCA7 in Brain Homeostasis and Alzheimer’s Disease

Genetic and environmental factors influence the risk of late-onset Alzheimer’s disease; genetic studies have identified novel risk genes for the disease. ABCA7 is the gene encoding ATP-binding cassette sub-family A member 7; variants of ABCA7, which shares a homology with ABCA1, have shown a strong association with increased risk for late-onset Alzheimer’s disease. Importantly, loss-of-function variants in ABCA7 also have been demonstrated to significantly increase Alzheimer’s disease risk. While ABCA7 is expressed in neurons and microglia in the brain, our knowledge of ABCA7 function in those cell types is limited. Our recent studies using knockout mice have implicated novel functions of ABCA7 in regulating amyloid beta production, cellular stress responses and the brain’s immune system. Thus, we will further investigate how cell type-specific ABCA7 loss of function impacts known Alzheimer’s disease-related pathways, to identify novel ones through nontargeted approaches. Specifically, we will examine ABCA7 function using primary neurons and microglia/macrophages using human-induced pluripotent stem cell (iPSC) models. We currently are generating iPSC lines where the ABCA7 gene is edited by CRISPR/Cas9 technology to model disease-associated mutations. We also are generating neuron- or microglia-specific ABCA7 knockout mice. Using these new models, we will comprehensively investigate how ABCA7 in each cell type regulates brain homeostasis, and how disturbances of these mechanisms contribute to the development of Alzheimer’s disease. Our studies should lead to new therapeutic strategies targeting ABCA7 in Alzheimer’s disease.