Introduction
A rare coding variant (S209F) in ABI3 (Abelson interactor family member 3), a core microglial component of the WAVE2 actin-regulatory complex, increases the risk of late-onset Alzheimer’s disease (AD). However, the mechanistic contribution of ABI3 to AD pathology remains poorly defined.
Aim
To determine whether loss of Abi3 function opposes the effects of the AD-associated Abi3 risk variant and to assess the therapeutic potential of Abi3 inhibition in vivo.
Methods
AD-related pathology was examined in the physiologically relevant AppNL-G-F knock-in mouse model under conditions of Abi3 deficiency or expression of Abi3F212 (murine equivalent of the human S209F variant). Microglial morphology, lysosomal activation, amyloid pathology, synaptic integrity, and cognition were assessed using established histological, imaging, and behavioural approaches (n = 16 mice per genotype across assays, sex-balanced, aged to 2 and 6 months). Statistical comparisons were performed using mixed model regression. All animal procedures were conducted in accordance with institutional ethical guidelines.
Results
In the absence of disease, Abi3 deficiency resulted in a marked reduction in microglial ramification and territory, accompanied by increased microglial density and elevated CD68 immunoreactivity, whereas Abi3F212 expression produced modest increases in microglial arborisation. On the AppNL-G-F background, Abi3 deficiency directionally opposed the effects of the Abi3 risk variant. Abi3-deficient mice exhibited a pronounced reduction in amyloid burden compared with AppNL-G-F controls, while amyloid pathology was increased in Abi3F212-expressing mice. Behaviourally, Abi3 deficiency was associated with selective improvements in cognitive performance, with corresponding impairments observed following expression of Abi3F212. Mechanistically, the beneficial effects of Abi3 deficiency were associated with preservation of synaptic integrity in amyloid-associated regions and a substantial reduction in dynamic microglial parenchymal surveillance.
Conclusion
Loss of Abi3 function directionally opposes the pathogenic effects of the AD-associated Abi3 risk variant, resulting in reduced amyloid burden, improved cognitive outcomes, and protection against disease-associated synapse loss. These findings support ABI3 inhibition as a potential therapeutic strategy for Alzheimer’s disease.