The Impact of Mutations in the Ligand-Binding Domain of CD33 on Alzheimer’s Disease Pathogenesis

2024

Genetic studies of Alzheimer’s disease (AD) have revealed many AD-associated genes involved with innate immunity and microglial function, including CD33. We previously showed that the innate immune receptor CD33 inhibits microglial uptake and clearance of amyloid beta, a process that requires the ligand-binding domain. To understand the role of CD33 mutations in AD pathogenesis, we generated humanized CD33 mouse models that carry either wild-type CD33 or an AD-associated mutation in the ligand-binding domain. We showed that both wild-type and mutant CD33 are expressed in microglia surrounding amyloid beta plaques in humanized CD33 mouse models crossed to the 5xFAD mouse model of AD. Furthermore, we are currently investigating the effects of CD33 mutations in the ligand-binding domain on amyloid beta accumulation, neurodegeneration and neuroinflammation in humanized CD33 mouse models crossed to 5xFAD mice. This study on the functional analysis of CD33 mutations in humanized mouse models may reveal novel aspects of CD33 function in microglia and facilitate AD therapeutics targeting this receptor.

2023

We previously showed that the innate immune receptor CD33 inhibits brain amyloid beta clearance, a process that requires the ligand-binding domain. Our analysis of Alzheimer’s disease (AD) genetic datasets identified novel CD33 gene variants that are associated with AD. We generated humanized CD33 mouse models that carry either wild-type CD33 or an AD-associated mutation in the ligand-binding domain of CD33. We showed that both wild-type and mutant CD33 exhibited prominent expression in microglia that cluster around amyloid beta plaques in humanized CD33 mouse models crossed to the 5xFAD mouse model of AD. Here, we will investigate the effects of CD33 mutations in the ligand-binding domain on amyloid beta pathology, neurodegeneration and microglial cell recruitment to plaques in humanized CD33 mouse models crossed to 5xFAD mice. The proposed study will elucidate molecular mechanisms underlying microglial pathology in AD and facilitate the development of personalized treatment for AD patients carrying CD33 mutations.