Understanding how ABI3 contributes to the aetiology of Alzheimer's disease

We hypothesize that the rare ABI3 variant promotes the development of Alzheimer's disease through altered macrophage, specifically microglial, homeostatic function. Understanding how ABI3 contributes to the aetiology of Alzheimer's disease will provide novel insights into the mechanisms underlying the transition from genetic susceptibility to development of disease.

In an effort to better understand the biology of AD susceptibility, the Cardiff group have been using exome arrays to detect coding variation in genes, information which is more tractable in downstream experimentation, to work out the underlying biology of the disease. One such variant lies in ABI3, a little studied gene. The encoded protein product, ABI3, is part of a network of 151 genes that have been detected as central to AD susceptibility. These genes are the overlap of four immune-related co-expression modules, each of which is significantly enriched for association signal in the International Genomics of Alzheimer's Project (IGAP) GWAS. The module overlap captures the association enrichment observed in the modules 5. Further work indicates that these 151 genes show a significant excess of high-confidence protein-protein interactions in the STRING protein interaction database (http://string-db.org/). In particular, 56 genes form an interaction network (which itself is significantly larger than would be expected by chance, given the overall numbers of protein-protein interactions observed for the 151 genes in the module overlap) and these 56 genes capture most of the IGAP GWAS signal enrichment observed in the module overlap: ABI3 is part of this network. Importantly, TREM2 and CSFR1, also implicated in susceptibility to or treatment of AD are part of the same network 6-8. This provides convincing evidence for the involvement of ABI3 in immune processes relevant to the aetiology of AD, despite the relative lack of such annotations in public databases such as Gene Ontology, due to the lack of knowledge of its function.

ABI family member 3 (ABI3): The function of ABI3 (previously known as NESH) is far from understood. Early studies indicated that overexpression of ABI3 led to a reduction in cell motility and reduced metastasis in an in vivo cancer model attributed to an apparent interaction with p21 activated kinase. Whilst this study did not demonstrate an impact on cell proliferation, subsequent study of both ABI3 and ABI3BP (ABI3 binding protein), reported an impact of its expression on proliferation as well as in vivo cancer cell growth. These tumour suppressing roles for ABI3 are interesting in the context of observed low expression of ABI3 in cancer cells. Given the association we have identified between ABI3 polymorphisms and the development of AD, the contribution of ABI3 to the aetiology of the disease and whether it is attributable to alterations in cell growth and adhesion/migration or otherwise unknown functions are urgent unaddressed questions. In addition, the Abi3-deficient mouse is so recently generated that its phenotype was not characterised. We have imported the Abi3-deficient allele in heterozygous state and recently confirmed that the homozygote is viable and apparently normal in gross appearance.