Lithium Reduces BACE1 Overexpression, Beta Amyloid Accumulation, and Spatial Learning Deficits in Mice with Traumatic Brain Injury

Abstract 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 hippocamp...