Fig. 11

Hypothetical scenarios linking Abi3-Gngt2 function to AD. a Tabulated view of neuropathological findings in Abi3-Gngt2^−/− mice relative to Abi3-Gngt2^+/+ mice. n.d., not done. b Schematic summary of possible Abi3/Gngt2 function in the context of AD. Our experiments with Abi3-Gngt2 deficient model show that immune phenotype in these mice reduce Aβ plaques in a gene dose- and age-dependent manner in TgCRND8 mice but increase tau phosphorylation in AAV-tau model (i). Loss of Abi3-Gngt2 function leads to early-life induction of AD/amyloid-associated factors and microglial genetic risk factors, independent of Aβ. In fact, these same microglial factors (as tabulated in i) are altered as humans progress from healthy status to AD (ii). Based on our data, we hypothesize that a normally functioning Abi3 would lead to suppression of immunity (by suppressing induction of AD disease microglial risk factor genes), thus increasing Aβ plaques but preventing tau phosphorylation and tangle formation (iii). Whether this would modulate synaptic resilience and dementia progression resulting in protective effects requires further investigation. The neuropathology in the Abi3-Gngt2 deficient model is reminiscent of the dichotomy observed in multiple AD mouse models. The differential response of Aβ and tau to immune activation necessitates a cautious foray into immune-targeted therapies. Future work in rodent models of Aβ deposition and tau pathology in the presence of the S209F mutated Abi3 would provide critical functional information. Our in vitro data shows that the AD associated S209F mutation dramatically reduces self-phosphorylation, which guided by previous data from ABI family of proteins, would imply a loss of function phenotype (iv). Brain picture (ii) adapted from online source under CC license