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

[ Vol. 15 , Issue. 13 ]

Author(s):

Edward N. Wilson, Sonia Do Carmo, M. Florencia Iulita, Hélène Hall, Grant L. Austin, Dan T. Jia, Janice C. Malcolm, Morgan K. Foret, Adam R. Marks, D. Allan Butterfield and A. Claudio Cuello*   Pages 1220 - 1230 ( 11 )

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.

Keywords:

Alzheimer's disease, oxidative stress, inflammation, microdose lithium, microglia, TREM2.

Affiliation:

Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Department of Chemistry, University of Kentucky, Lexington, KY 40506, Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Department of Chemistry, University of Kentucky, Lexington, KY 40506, Department of Pharmacology and Therapeutics, McGill University, Montreal, QC



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