Title:Microdose Lithium NP03 Diminishes Pre-Plaque Oxidative Damage and Neuroinflammation in a Rat Model of Alzheimer’s-like Amyloidosis
Volume: 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*
Affiliation:
- Department of Pharmacology and Therapeutics, McGill University, Montreal, QC,Canada
Keywords:
Alzheimer's disease, oxidative stress, inflammation, microdose lithium, microglia, TREM2.
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.
