Understanding how ABI3 contributes to the aetiology of Alzheimer’s Disease

Simonazzi, Elena 2022. Understanding how ABI3 contributes to the aetiology of Alzheimer’s Disease. PhD Thesis, Cardiff University. Item availability restricted.

Preview	PDF - Accepted Post-Print Version Download (15MB) | Preview
	PDF (Cardiff University Electronic Publication Form) - Supplemental Material Restricted to Repository staff only Download (164kB)

Abstract

Neuroinflammation in Alzheimer’s Disease (AD) is not a simple by-product of β-amyloidosis and neurofibrillary tangles, but it rather plays a crucial role in AD pathogenesis. However, we are still far from understanding how exactly microglia influence disease progression. A rare missense variant, S209F, associated to an increased risk of AD has been identified in Abi3 (Abl-interactor-3), a poorly investigated member of the Abi family, which is involved in Rac-dependent regulation of the actin cytoskeleton. Within the brain, Abi3 is considered a core human microglial signature gene. Given that a flexible actin cytoskeleton is key to many microglia – and more broadly, macrophages – functions, the precise role of Abi3 in these cells in health and pathology, such as AD, needs to be clarified. In order to investigate Abi3 biological functions, a combination of cellular assays, histology, live imaging and behavioural paradigms was employed. In an actin-mediated spreading assay, Abi3 knock-out (KO) BMDM-like cells – derived from conditionally-immortalized macrophage precursors – showed increased cellular surface and solidity. These findings have been validated by histological analyses of brains of healthy Abi3-WT and -KO mice as well as in the APPNL-G-F AD model. Microglial cells lacking Abi3 present reduced ramifications accompanied by an increase in cell density and CD68 expression. Young Abi3-KO mice also show impaired surveyance activity in vivo. In addition, Abi3 ablation leads to an elevated astrocytic density from a young age, as well as a reduction in Amyloid β deposition in the hippocampus, but not in the prefrontal cortex, of 16-week-old mice. Behavioural assays highlighted a potential impact of Abi3 ablation on the emotional domain but not on cognitive ability. These results support the hypothesis of a critical role of Abi3 in microglial homeostasis, and suggest that its rare variant may promote AD development by altering microglia homeostatic functions.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Medicine
Date of First Compliant Deposit:	8 July 2022
Last Modified:	07 Jul 2023 01:30
URI:	https://orca.cardiff.ac.uk/id/eprint/151106

Actions (repository staff only)

Edit Item