Lithium mitigates hippocampal tau pathology in a rodent model of traumatic brain injury.

Repetitive traumatic brain injury (TBI) is the main risk factor for chronic traumatic encephalopathy (CTE), a neurodegenerative disease that is defined by pathological inclusions of phosphorylated tau protein located at the depths of the cortical sulci and surrounding blood vessels. The cellular mechanisms involved in tau phosphorylation are upregulated by TBI, leading to increased levels of misfolded tau, which can progress to form insoluble aggregates and drive the progression of CTE. Targeting tau phosphorylation is thus an appealing strategy for reducing tau aggregation and preventing CTE. The phosphorylation of tau at Thr231 is a crucial step that promotes aberrant tau misfolding and fibril formation that occurs following TBI and in CTE. Lithium, known for its neuroprotective effects, has previously been shown to reduce tau phosphorylation. However, its effect on Thr231 in the context of TBI is unknown. In this study, we investigated the therapeutic potential of lithium on tau phosphorylation in a rodent model of TBI. Female adult rats subjected to a single TBI were administered daily lithium and histologically assessed for tau pathology, neuroinflammation, and neurodegeneration. In TBI animals, pThr231 tau pathology progressively increased throughout the hippocampus over the first 10 days and was associated with a loss of Calbindin 1 and an increase in mitochondrial calcium uniporter (MCU) expression. Lithium treatment reduced hippocampal pThr231 tau pathology and microgliosis at day 10 post-TBI. In lithium-treated TBI animals, the loss of Calbindin 1 was prevented and the level of MCU was decreased in regions associated with reduced pThr231 tau pathology. In CTE, the level of Calbindin 1 was similarly decreased in the presence of pThr231-positive neurofibrillary tangles. These findings demonstrate that lithium is effective in reducing hippocampal pThr231 tau pathology and attenuating neuroinflammation in TBI, accompanied by maintaining physiological expression of Calbindin 1 and MCU.