Article type: Research Article

Authors: Wilson, Edward N.a | Do Carmo, Soniab | Welikovitch, Lindsay A.b | Hall, Hélèneb | Aguilar, Lisi Floresb | Foret, Morgan K.b | Iulita, M. Florenciab | Jia, Dan Tongb | Marks, Adam R.b | Allard, Simonb | Emmerson, Joshua T.b | Ducatenzeiler, Adrianab | Cuello, A. Claudioa; b; c; d; *

Affiliations: [a] Neurology and Neurosurgery, McGill University, Montreal Neurological Institute, Montreal, QC, Canada | [b] Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada | [c] Anatomy and Cell Biology, McGill University, Montreal, QC, Canada | [d] Department of Pharmacology, University of Oxford, Oxford, United Kingdom (Visiting Professorship)

Correspondence: [*] Correspondence to: A. Claudio Cuello, Department of Pharmacology and Therapeutics, McGill University, 3655 Sir-William Osler Promenade, Montreal, Quebec, H3G 1Y6, Canada. E-mail: [email protected].

Abstract: Epidemiological, preclinical, and clinical studies have suggested a role for microdose lithium in reducing Alzheimer’s disease (AD) risk by modulating key mechanisms associated with AD pathology. The novel microdose lithium formulation, NP03, has disease-modifying effects in the McGill-R-Thy1-APP transgenic rat model of AD-like amyloidosis at pre-plaque stages, before frank amyloid-β (Aβ) plaque deposition, during which Aβ is primarily intraneuronal. Here, we are interested in determining whether the positive effects of microdose lithium extend into early Aβ post-plaque stages. We administered NP03 (40μg Li/kg; 1 ml/kg body weight) to McGill-R-Thy1-APP transgenic rats for 12 weeks spanning the transition phase from plaque-free to plaque-bearing. The effect of NP03 on remote working memory was assessed using the novel object recognition task. Levels of human Aβ38, Aβ40, and Aβ42 as well as levels of pro-inflammatory mediators were measured in brain-extracts and plasma using electrochemiluminescent assays. Mature Aβ plaques were visualized with a thioflavin-S staining. Vesicular acetylcholine transporter (VAChT) bouton density and levels of chemokine (C-X-C motif) ligand 1 (CXCL1), interleukin-6 (IL-6), and 4-hydroxynonenal (4-HNE) were probed using quantitative immunohistochemistry. During the early Aβ post-plaque stage, we find that NP03 rescues functional deficits in object recognition, reduces loss of cholinergic boutons in the hippocampus, reduces levels of soluble and insoluble cortical Aβ42 and reduces hippocampal Aβ plaque number. In addition, NP03 reduces markers of neuroinflammation and cellular oxidative stress. Together these results indicate that microdose lithium NP03 is effective at later stages of amyloid pathology, after appearance of Aβ plaques.

Keywords: Aβ pathology, Alzheimer’s disease, brain repair, cholinergic boutons, cognition, lithium microdose, neuroinflammation, oxidative stress, transgenic rat model

DOI: 10.3233/JAD-190862

Journal: Journal of Alzheimer's Disease, vol. 73, no. 2, pp. 723-739, 2020