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 proteinopathy 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 by glycogen synthase kinase-3 β (GSK3β) is a crucial step that promotes aberrant tau misfolding and fibril formation. We have previously demonstrated that GSK3β inhibition with lithium prevents pThr231-associated fibril formation in vitro and that pThr231 tau is increased in experimental TBI. Given this, we investigated the therapeutic potential and neuroprotective properties of lithium 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. Lithium treatment reduced hippocampal pThr231 tau pathology and microgliosis at day 10 post-TBI. Furthermore, pThr231 tau pathology was uniquely associated with altered expression of Calbindin 1 and mitochondrial calcium uniporter (MCU). In TBI animals, hippocampal pThr231 tau pathology was most often observed in Calbindin 1-negative and MCU-positive neurons. In contrast, lithium treatment increased the level of Calbindin 1 and decreased the level of MCU in association with reduced pThr231 tau pathology. In CTE, we also observed an increase in pathological pThr231 tau and a decrease in Calbindin 1-expressing cells in the hippocampus, suggesting that calcium dysregulation is relevant to human tauopathy. Overall, we have demonstrated that lithium is effective in reducing hippocampal pThr231 tau pathology by inhibiting GSK3β, attenuating neuroinflammation, and maintaining calcium homeostasis.