Deletion of Abi3/Gngt2 influences age-progressive amyloid β and tau pathologies in distinctive ways

Abstract

Background The S209F variant of Abelson Interactor Protein 3 (ABI3) increases risk for Alzheimer’s disease (AD), but little is known about its function in relation to AD pathogenesis. Methods Here, we use a mouse model that is deficient in Abi3 locus to study how the loss of function of Abi3 impacts two cardinal neuropathological hallmarks of AD—amyloid β plaques and tau pathology. Our study employs extensive neuropathological and transcriptomic characterization using transgenic mouse models and adeno-associated virus-mediated gene targeting strategies. Results Analysis of bulk RNAseq data confirmed age-progressive increase in Abi3 levels in rodent models of AD-type amyloidosis and upregulation in AD patients relative to healthy controls. Using RNAscope in situ hybridization, we localized the cellular distribution of Abi3 in mouse and human brains, finding that Abi3 is expressed in both microglial and non-microglial cells. Next, we evaluated Abi3−/− mice and document that both Abi3 and its overlapping gene, Gngt2, are disrupted in these mice. Using multiple transcriptomic datasets, we show that expression of Abi3 and Gngt2 are tightly correlated in rodent models of AD and human brains, suggesting a tight co-expression relationship. RNAseq of the Abi3-Gngt2−/− mice revealed upregulation of Trem2, Plcg2, and Tyrobp, concomitant with induction of an AD-associated neurodegenerative signature, even in the absence of AD-typical neuropathology. In APP mice, loss of Abi3-Gngt2 resulted in a gene dose- and age-dependent reduction in Aβ deposition. Additionally, in Abi3-Gngt2−/− mice, expression of a pro-aggregant form of human tau exacerbated tauopathy and astrocytosis. Further, using in vitro culture assays, we show that the AD-associated S209F mutation alters the extent of ABI3 phosphorylation. Conclusions These data provide an important experimental framework for understanding the role of Abi3-Gngt2 function and early inflammatory gliosis in AD. Our studies also demonstrate that inflammatory gliosis could have opposing effects on amyloid and tau pathology, highlighting the unpredictability of targeting immune pathways in AD.

Identification and Quantitation of Novel ABI3 Isoforms Relative to Alzheimer’s Disease Genetics and Neuropathology

“…At this time, the actions of both SNPs are unclear. However, the substitution of a Phe for a Ser at 209 was recently found to affect ABI3 phosphorylation [ 7 ]. Regarding rs28394864, ABI3 was apparently identified as the best candidate gene for this SNP, because ABI3 had previously been implicated in AD by S209F and is in the vicinity of rs28394864 [ 2 , 4 , 5 ].…”

“…Considering the overall role of ABI3 in AD, we note that (i) the S209F SNP is associated with increased AD risk [ 2 , 3 , 18 ] and reduced ABI3 phosphorylation [ 7 ], and (ii) reduced ABI3 phosphorylation appears to increase ABI3 function [ 17 ]. Hence, we hypothesize that AD risk may be promoted by increased ABI3 function.…”

“…This model could be tested in a murine model comparing both alleles of S209F in ABI3 . Although results from this approach are not yet available, two studies with murine Abi3 knockout models have been reported [ 7 , 40 ]. Both involve beta amyloid accumulation in a model that includes deletion of the Abi3 locus, which also contains Gngt2 .…”

“…Both involve beta amyloid accumulation in a model that includes deletion of the Abi3 locus, which also contains Gngt2 . Unfortunately, these studies yielded inconsistent results, with Karahan et al finding that Abi3 locus deletion resulted in increased amyloid burden in 5xFAD mice, while Ibanez et al found that Abi3 locus deletion reduced amyloid burden in TgCRND8 mice [ 7 , 40 ]. Interestingly, Ibanez et al also found that Abi3 locus deletion exacerbated tau accumulation and inflammation in a murine model of tau aggregation [ 7 ].…”

“…ABI3 is expressed primarily by microglia in the human brain [ 6 , 7 ]. Our understanding of the actions of microglia in AD is evolving, but microglia are currently believed to play a biphasic role in AD.…”