Deletion of Abi3/Gngt2 influences age-progressive amyloid β and tau pathologies in distinctive ways.
Alzheimers Res Ther
washington; isb; Adaptor Proteins, Signal Transducing; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloidosis; Animals; Brain; Disease Models, Animal; GTP-Binding Protein gamma Subunits; Gliosis; Humans; Membrane Glycoproteins; Mice; Mice, Transgenic; Plaque, Amyloid; Receptors, Immunologic; tau Proteins
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
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.
Neurosciences (Brain & Spine)
Institute for Systems Biology
Ibanez, Kristen R; McFarland, Karen N; Phillips, Jennifer; Allen, Mariet; Lessard, Christian B; Zobel, Lillian; De La Cruz, Elsa Gonzalez; Shah, Shivani; Vo, Quan; Wang, Xue; Quicksall, Zachary; Ryu, Daniel; Funk, Cory C; Ertekin-Taner, Nilüfer; Prokop, Stefan; Golde, Todd E; and Chakrabarty, Paramita, "Deletion of Abi3/Gngt2 influences age-progressive amyloid β and tau pathologies in distinctive ways." (2022). Articles, Abstracts, and Reports. 6438.