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

Autor: Ibanez KR; Center for Translational Research in Neurodegenerative Disease, University of Florida, 1275 Center Drive, Gainesville, FL, 32610, USA., McFarland KN; Center for Translational Research in Neurodegenerative Disease, University of Florida, 1275 Center Drive, Gainesville, FL, 32610, USA.; Department of Neurology, University of Florida, Gainesville, FL, 32610, USA., Phillips J; Center for Translational Research in Neurodegenerative Disease, University of Florida, 1275 Center Drive, Gainesville, FL, 32610, USA., Allen M; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA., Lessard CB; Center for Translational Research in Neurodegenerative Disease, University of Florida, 1275 Center Drive, Gainesville, FL, 32610, USA., Zobel L; Center for Translational Research in Neurodegenerative Disease, University of Florida, 1275 Center Drive, Gainesville, FL, 32610, USA., De La Cruz EG; Center for Translational Research in Neurodegenerative Disease, University of Florida, 1275 Center Drive, Gainesville, FL, 32610, USA., Shah S; Center for Translational Research in Neurodegenerative Disease, University of Florida, 1275 Center Drive, Gainesville, FL, 32610, USA., Vo Q; Center for Translational Research in Neurodegenerative Disease, University of Florida, 1275 Center Drive, Gainesville, FL, 32610, USA., Wang X; Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, FL, 32224, USA., Quicksall Z; Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, FL, 32224, USA., Ryu D; Center for Translational Research in Neurodegenerative Disease, University of Florida, 1275 Center Drive, Gainesville, FL, 32610, USA., Funk C; Institute for Systems Biology, Seattle, WA, 98109, USA., Ertekin-Taner N; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.; Department of Neurology, Mayo Clinic, Jacksonville, FL, 32224, USA., Prokop S; Center for Translational Research in Neurodegenerative Disease, University of Florida, 1275 Center Drive, Gainesville, FL, 32610, USA.; Department of Pathology, University of Florida, Gainesville, FL, 32610, USA.; McKnight Brain Institute, University of Florida, Gainesville, FL, 32610, USA., Golde TE; Center for Translational Research in Neurodegenerative Disease, University of Florida, 1275 Center Drive, Gainesville, FL, 32610, USA.; McKnight Brain Institute, University of Florida, Gainesville, FL, 32610, USA.; Department of Neuroscience, University of Florida, Gainesville, FL, 32610, USA., Chakrabarty P; Center for Translational Research in Neurodegenerative Disease, University of Florida, 1275 Center Drive, Gainesville, FL, 32610, USA. pchakrabarty@ufl.edu.; McKnight Brain Institute, University of Florida, Gainesville, FL, 32610, USA. pchakrabarty@ufl.edu.; Department of Neuroscience, University of Florida, Gainesville, FL, 32610, USA. pchakrabarty@ufl.edu.
Jazyk: angličtina
Zdroj: Alzheimer's research & therapy [Alzheimers Res Ther] 2022 Jul 27; Vol. 14 (1), pp. 104. Date of Electronic Publication: 2022 Jul 27.
DOI: 10.1186/s13195-022-01044-1
Abstrakt: 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje