Microdose Lithium NP03 Diminishes Pre-Plaque Oxidative Damage and Neuroinflammation in a Rat Model of Alzheimer’s-like Amyloidosis

Abstract

Background: Microdose lithium is protective against Alzheimer’s disease (AD), although the precise mechanisms through which its protective effects are conferred remain unclear. Objective: To further examine the effects during the earliest stages of Aβ pathology, we evaluated whether NP03, a microdose lithium formulation, modulates Aβ-mediated oxidative damage and neuroinflammation when applied to a rat transgenic model of AD-like amyloidosis overexpressing amyloid precursor protein (APP). Method: McGill-R-Thy1-APP transgenic rats and wild-type littermates were treated with NP03 or vehicle formulation for 8 weeks beginning at 3 months of age - a phase preceding Aβ plaque deposition in the transgenic rats. Results: Oxidative and nitrosative stress markers, protein-bound 4-hydroxynonenal (HNE) and proteinresident 3-nitrotyrosine (3-NT), inflammatory cytokines production, as well as microglial recruitment towards Aβ-burdened neurons were assayed. NP03 significantly decreased cerebral HNE and 3-NT, and reduced production of pro-inflammatory cytokines in McGill-R-Thy1-APP transgenic rats. NP03 further reduced expression of microglia surface receptor Trem2 and led to a corresponding reduction in microglia recruitment towards Aβ-burdened neurons in the CA1 region of the hippocampus. Conclusion: These results suggest that NP03 may function to slow the AD-like pathology in part by modifying oxidative/nitrosative damage and neuroinflammation, raising the possibility that low doses of microencapsulated lithium might be of therapeutic-preventive value during very early or preclinical AD.