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

Ibanez, K.; McFarland, K.; Phillips, J.; Allen, M.; Lessard, C. B.; Zobel, L.; Gonzalez De La Cruz, E.; Shah, S.; Vo, Q.; Wang, X.; Quicksall, Z.; Ryu, D.; Funk, C.; Ertekin-Taner, N.; Prokop, S.; Golde, T.; Chakrabarty, P.

doi:10.1101/2021.11.08.467701

bioRxiv · 10.1101/2021.11.08.467701

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

Ibanez, K.·McFarland, K.·Phillips, J.·Allen, M.·Lessard, C. B.·Zobel, L.·Gonzalez De La Cruz, E.·Shah, S.·Vo, Q.·Wang, X.·Quicksall, Z.·Ryu, D.·Funk, C.·Ertekin-Taner, N.·Prokop, S.·Golde, T.·Chakrabarty, P.

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Abstract

The S209F variant of Abelson Interactor Protein 3 (ABI3) increases risk for Alzheimers disease (AD), but little is known about ABI3 function. RNAscope showed Abi3 is expressed in microglial and non-microglial cells, though its increased expression appears to be driven in plaque-associated microglia. Here, we evaluated Abi3-/- mice and document that both Abi3 and its overlapping gene, Gngt2, are disrupted in these mice. Expression of Abi3 and Gngt2 are tightly correlated, and elevated, in rodent models of AD. RNA-seq of the Abi3-Gngt2-/- mice revealed robust induction of an AD-associated neurodegenerative signature, including upregulation of Trem2, Plcg2 and Tyrobp. In APP mice, loss of Abi3-Gngt2 resulted in a gene dose- and age-dependent reduction in A{beta} deposition. Additionally, in Abi3-Gngt2-/- mice, expression of a pro-aggregant form of human tau exacerbated tauopathy and astrocytosis. Further, the AD-associated S209F mutation alters the extent of ABI3 phosphorylation. These data provide an important experimental framework for understanding the role of Abi3-Gngt2 function in AD. Our studies also demonstrate that manipulation of glial function could have opposing effects on amyloid and tau pathology, highlighting the unpredictability of targeting such pathways in AD.

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Ibanez, K., McFarland, K., Phillips, J., Allen, M., Lessard, C. B., Zobel, L., Gonzalez De La Cruz, E., Shah, S., Vo, Q., Wang, X., Quicksall, Z., Ryu, D., Funk, C., Ertekin-Taner, N., Prokop, S., Golde, T., Chakrabarty, P.. 2021-11-09. Deletion of Abi3/Gngt2 influences age-progressive amyloid β and tau pathologies in distinctive ways. https://doi.org/10.1101/2021.11.08.467701

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