The effect of Abi3 locus deletion on the progression of Alzheimer’s disease-related pathologies

Abstract

Human genetics studies of Alzheimer's disease (AD) have identified the <i>ABI3</i> gene as a candidate risk gene for AD. Because <i>ABI3</i> is highly expressed in microglia, the brain's immune cells, it was suggested that ABI3 might impact AD pathogenesis by regulating the immune response. Recent studies suggest that microglia have multifaceted roles in AD. Their immune response and phagocytosis functions can have beneficial effects in the early stages of AD by clearing up amyloid-beta (Aβ) plaques. However, they can be harmful at later stages due to their continuous inflammatory response. Therefore, it is important to understand the role of genes in microglia functions and their impact on AD pathologies along the progression of the disease. To determine the role of ABI3 at the early stage of amyloid pathology, we crossed <i>Abi3</i> knock-out mice with the 5XFAD Aβ-amyloidosis mouse model and aged them until 4.5-month-old. Here, we demonstrate that deletion of the <i>Abi3</i> locus increased Aβ plaque deposition, while there was no significant change in microgliosis and astrogliosis. Transcriptomic analysis indicates alterations in the expression of immune genes, such as <i>Tyrobp</i>, <i>Fcer1g</i>, and <i>C1qa</i>. In addition to the transcriptomic changes, we found elevated cytokine protein levels in <i>Abi3</i> knock-out mouse brains, strengthening the role of ABI3 in neuroinflammation. These findings suggest that loss of ABI3 function may exacerbate AD progression by increasing Aβ accumulation and inflammation starting from earlier stages of the pathology.