Modulation of neuroinflammation and tauopathy by RNA-binding protein TIA1 in the P301S mouse model of tauopathy
LeBlang, Chelsey Jenna
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Tauopathies are a class of neurodegenerative diseases characterized by aggregation of hyperphosphorylated microtubule associated protein tau (phospho-tau), resulting in neuroinflammation and neurodegeneration. Neuroinflammatory processes play an integral role in the exacerbation and progression of pathology in these disorders, leading to increased levels of neurodegeneration. The RNA binding protein (RBP) T-cell Intracellular Antigen 1 (TIA1) is an important regulator of the innate immune response in the periphery, dampening cytotoxic inflammation and apoptosis during cellular stress, however its role in central neuroinflammation is unclear. We have recently shown that TIA1 regulates tau pathophysiology and toxicity in part through the binding of phospho-tau oligomers into pathological stress granules. Haploinsufficiency of TIA1 in the P301S mouse model of tauopathy results in reduced accumulation of toxic tau oligomers, pathologic stress granules, and the development of downstream pathological features of tauopathy. The putative role of TIA1 as a regulator of the peripheral immune response led us to characterize the role of TIA1 in neuroinflammation, and determine its relationship with neurodegeneration in the context of tauopathy, a chronic stressor in the neural environment. Here, we evaluated indicators of neuroinflammation (reactive microgliosis and phagocytosis, pro-inflammatory cytokine release, and oxidative stress), and neurodegeneration (gross hippocampal atrophy, neuronal loss, synapse loss, and phospho-tau load) in wildtype and P301S transgenic mice expressing TIA1+/+, TIA1+/-, and TIA1-/- in both early (5 month) and advanced (9 month) disease states through biochemical, ultrastructural, and histological analyses. Our data show that both TIA1 haploinsufficiency and TIA1 knockout exacerbate neuroinflammatory processes in advanced stages of tauopathy, suggesting that TIA1 dampens the immune response in the central nervous system during chronic stress. TIA1 haploinsufficiency and knockout do not reduce neurodegeneration in advanced disease, and importantly, TIA1 knockout exacerbates neuron and synapse loss in hippocampal regions. With both increased levels of neuroinflammation and neurodegeneration, P301S animals with TIA1 knockout are distinct from age-matched P301S and wildtype mice. This study demonstrates that TIA1 plays an important role in the regulation of innate immune response in neurodegenerative disease, and its expression significantly impacts the progression of tauopathy.