Microdose lithium NP03 diminishes pre-plaque oxidative damage and neuroinflammation in a rat model of alzheimer’s-like amyloidosis

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, A. Claudio Cuello

Research output: Contribution to journalArticlepeer-review

16 Scopus citations


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 protein-resident 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.

Original languageEnglish
Pages (from-to)1220-1230
Number of pages11
JournalCurrent Alzheimer Research
Issue number13
StatePublished - 2018

Bibliographical note

Funding Information:
This work was supported by grants from the Canadian Institutes of Health Research (grant number 102752). SDC is the holder of the Charles E. Frosst/Merck Research Associate position. MFI was the recipient of a Biomedical Doctoral Award from the Alzheimer Society of Canada. HH is the holder of a Fonds de la Recherche en Santé Québec Postdoctoral Fellowship. ACC is the holder of the Charles E. Frosst/Merck-endowed Chair in Pharmacology and is a Team Leader for the Canadian Consortium on Neurodegeneration in Aging. We wish to thank Dr. Alan Frosst, the Frosst family, and Merck Canada for their continuing support.

Publisher Copyright:
© 2018 Bentham Science Publishers.


  • Alzheimer’s disease
  • Inflammation
  • Microdose lithium
  • Microglia
  • Oxidative stress
  • TREM2

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology


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