Studying the Functional Consequences of Alzheimer’s Disease Risk Variants in the CLU and ABCA7 Genes Using Both Human and Mouse Models

The vast majority of people with Alzheimer’s disease (AD) suffer from the sporadic (late-onset) form, whose causes remain completely unknown. From studies involving thousands of people, researchers have identified a number of genetic variants that may increase one’s risk for sporadic AD (sAD). However, little is understood regarding how carrying these variants impacts one’s sAD risk.

To better understand the roles of genetic variants in sAD, we are using the cutting-edge genome editing technology of CRISPR/Cas9 and induced pluripotent stem cells (iPSCs) to engineer human stem cells to have mutations for two of the genes with the high risks for sAD: ABCA7 and CLU. We have used these iPSCs to generate brain-specific cell types, including neural progenitor cells, neurons, astrocytes and microglia.

We have discovered that neurons carrying a mutation of ABCA7 produce such AD-like cellular hallmarks as elevated levels of soluble amyloid beta and such abnormal organelles as enlarged early endosomes. We further show that ABCA7 mutant when incorporated into an engineered tissue-organ model displays such AD pathologies as accumulation of amyloid deposits seen in the brains of Alzheimer’s patients.

These exciting discoveries, when integrated with our planned comprehensive analysis from the other cell types, including microglia and astrocytes of the mutational effects of ABCA7 and CLU on AD pathologies and contribution of ABCA7 mutation to familial AD using the 5XFAD mouse model, will provide valuable insights into the molecular pathways by which these genetic risk variants contribute to sporadic AD.