Scientists have found that loss of ABI3 function, a protein-coding gene, may increase the risk of developing Alzheimer’s disease by affecting amyloid β accumulation and neuroinflammation.
Alzheimer’s disease (AD) is the most common cause of dementia. It is characterised by the abnormal accumulation of amyloid β as plaques, hyperphosphorylated tau in the form of neurofibrillary tangles and neuroinflammation in the brain. Microglia are the predominant immune cells of the brain. They promote clearance of amyloid β through phagocytosis and regulate brain immunity by secreting inflammatory cytokines in AD.
Genome-wide association studies (GWAS) of AD have identified many risk genes that are highly expressed in microglia. For example, a recent large-scale human genetics study identified a rare coding variant in the Abelson interactor family member 3 (ABI3) gene that was associated with an increased risk of late-onset AD. ABI3, a protein-coding gene, like many other AD risk variants, is highly expressed in the microglia. However, how microglial AD risk genes regulate the function of inflammatory cytokines remains elusive, and whether the variant in the ABI3 gene causes gain- or loss-of-function has yet to be discovered.
Investigating the role of ABI3
Recently, researchers at the Indiana University School of Medicine comprehensively investigated how ABI3 loss-of-function affects the pathological features of AD using the 5XFAD mouse model. Their findings, published in Science Advances, have provided valuable insights into the pathobiology of AD and are hoped to lead to the identification of new drug targets.
The team discovered that the deletion of ABI3 significantly increased amyloid β plaques, decreased microglia clustering around the plaques and dysregulated the immune response. Additionally, single-cell RNA sequencing revealed a shift in the proportion of certain microglia subpopulations in ABI3 knockout mice. Further analysis showed that knockdown of the ABI3 gene impaired the migration and phagocytosis of microglia.
Deleting the ABI3 gene
Overall, the data suggested that ABI3 affects the pathogenesis of AD by regulating microglia function and amyloid β pathology. This study has provided the first in vivo functional evidence that loss of ABI3 function may increase the risk of developing AD by affecting amyloid β accumulation and neuroinflammation. Therefore, determining the functional consequences of these microglia genetic risk factors may provide a valuable insight into the pathobiology of AD.
Moreover, ABI3 and its downstream pathways could be promising therapeutic targets for AD. Drug targets based on human genetics data are known to double the success rate in clinical development. AD GWAS variants are identified based on their association with disease risk, rather than the progression of AD. Therefore, it remains unknown how such variants may affect AD progression, which is important for the development of treatment. This could be particularly true for targeting microglia genes, as they may respond differently to AD pathology depending on the stage of the disease.
Hande Karahan, who led the study, said: “This study can provide further insight into understanding the key functions of microglia contributing to the disease and help identify new therapeutic targets”.
Image credit: The Conversation
