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Combined treatment with the microdose lithium formulation NP03 and S‐adenosylmethionine reduces cognitive decline and Alzheimer’s‐like amyloid pathology in Mcgill‐R‐Thy1‐APP rats
Author(s) -
Carmo Sonia Do,
Emmerson Joshua T.,
Foret Morgan K.,
Welikovitch Lindsay A.,
Cuello A. Claudio
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.043443
Subject(s) - neuroinflammation , medicine , cognitive decline , neurogenesis , lithium (medication) , genetically modified mouse , pharmacology , dementia , endocrinology , psychology , disease , neuroscience , transgene , chemistry , biochemistry , gene
Background By engaging several targets simultaneously, combination therapeutics hold promise for the prevention and treatment of complex conditions such as Alzheimer’s disease. We have previously shown that monotherapy using either NP03, a microemulsion formulation of lithium, which can reach the CNS when applied on mucosae, or S‐adenosylmethionine (SAM), a global methyl donor, can blunt amyloid‐driven pathology and cognitive impairment. Here, we explored the potential therapeutic value of a combination of NP03 and SAM in pre‐plaque McGill‐R‐Thy1‐APP transgenic (Tg) rats. Method We administered NP03 (rectal administration; 40 ug Li/Kg; 5 days per week), SAM (orally; 20 mg/Kg; 3 days per week), a combination of NP03‐SAM, or vehicle to 3‐month‐old Tg and non‐Tg control rats for 12 weeks. Behavioral testing and tissue harvest were performed 3 weeks after ceasing treatment. Results Combined NP03‐SAM treatment had a greater impact in reversing cognitive impairments in the auditory fear‐conditioning task compared with either the NP03 or SAM treatment alone. Moreover, NP03‐SAM‐treated McGill‐APP rats exhibited lower abundance of amyloid‐β peptides. Beneficial effects of NP03‐SAM treatment also included a reduction in neuroinflammation, BACE 1 expression and activity, and global DNA demethylation. Furthermore, combined treatment amplified the rescue of neurogenesis already observed in NP03‐treated rats. Conclusion Our findings provide preclinical evidence suggesting that combined treatment with NP03 and SAM may be of therapeutic value in the early stages of Alzheimer’s disease.