Lithium reduces BACE1 overexpression, β amyloid accumulation, and spatial learning deficits in mice with traumatic brain injury.

Traumatic brain injury (TBI) leads to both acute injury and long-term neurodegeneration, and is a major risk factor for developing Alzheimer's disease (AD). Beta amyloid (Aβ) peptide deposits in the brain are one of the pathological hallmarks of AD. Aβ levels increase after TBI in animal models and in patients with head trauma, and reducing Aβ levels after TBI has beneficial effects. Lithium is known to be neuroprotective in various models of neurodegenerative disease, and can reduce Aβ generation by modulating glycogen synthase kinase-3 (GSK-3) activity. In this study we explored whether lithium would reduce Aβ load after TBI, and improve learning and memory in a mouse TBI model. Lithium chloride (1.5 mEq/kg, IP) was administered 15 min after TBI, and once daily thereafter for up to 3 weeks. At 3 days after injury, lithium attenuated TBI-induced Aβ load increases, amyloid precursor protein (APP) accumulation, and β-APP-cleaving enzyme-1 (BACE1) overexpression in the corpus callosum and hippocampus. Increased Tau protein phosphorylation in the thalamus was also attenuated after lithium treatment following TBI at the same time point. Notably, lithium treatment significantly improved spatial learning and memory in the Y-maze test conducted 10 days after TBI, and in the Morris water maze test performed 17-20 days post-TBI, in association with increased hippocampal preservation. Thus post-insult treatment with lithium appears to alleviate the TBI-induced Aβ load and consequently improves spatial memory. Our findings suggest that lithium is a potentially useful agent for managing memory impairments after TBI or other head trauma.