Subtherapeutic dose lithium treatment induces behavioral and neuropathological changes in 3xTg‐AD Alzheimer's mice

Background: Alzheimer's disease (AD) is the most common cause of dementia and a global health challenge. The efficacy of lithium salts in stabilizing moods and neuroprotective effects has stimulated research into their use in neurodegenerative diseases. Method: We tested lithium carbonate treatment (1.0g Li ₂ CO ₃ /kg of chow; 12‐weeks) in 3xTg‐AD and age‐matched Wild‐Type male mice of 12‐month‐old. (CEUA/PROCESS: 1605/2020; 4127240122). Two behavioral test batteries were performed: (1) open‐field test (OFT), novel‐object recognition test (NORT), elevated zero‐maze test (EZMT), and Rotarod test; (2) tail‐suspension test (TST), forced‐swim test (FST), and sucrose preference test (SPT). Immunohistochemistry method was performed to analyze amyloid‐β (Aβ) accumulation (6E10), phosphorylated tau ( p ‐TaupSer199/202), and neuronal viability (neuronal nuclei; NeuN) in areas of the brain. Statistical analysis: two‐way ANOVA followed by Bonferroni post‐hoc test and unpaired t‐test; statistically significant p <0.05. Result: Neurobiological benefits of lithium treatment (mean serum lithium levels; Wild Type+Lithium, 0.22 mmol/L; 3xTg‐AD+Lithium, 0.27 mmol/L) caused improvement/preservation of object recognition memory (object recognition index in short‐ [F (1, 28) =8.37; p <0.01] and long‐term memory [F (1, 28) =7.99; p <0.01]). Lithium also caused improvements in anxiety (OFT [F (1, 28) =37.15; p <0.0001]; EZMT [F (1, 28) =19,44; p <0,001]), depression (TST [F (1, 28) =11.70; p <0.01]; FST [F (1, 28) =7.96; p <0.01]), and anhedonia (SPT [F (1, 24) =17,86; p <0,001]). The action of lithium was demonstrated in the 3xTgAD+Lithium group when compared to the 3xTg‐AD in reduction in amyloid load (parietal cortex [F(1, 21)=571,80; p <0,0001]; hippocampal area CA1 [F (1, 20) =417,90; p <0,0001]; dentate gyrus [F (1, 20) =417,74; p <0,001]; subiculum [F (1, 20) =1073,00; p <0,0001]; and amygdala [F (1, 22) =420,00; p <0,0001]) and phosphorylated tau (parietal cortex [F (1, 27) =845,20; p <0,0001]; hippocampal area CA1 [F (1, 27) =117,7; p <0,0001]; dentate gyrus [F (1, 27) =64,89; p <0,0001]; subiculum [F (1, 27) =76,46; p <0,0001]; and amygdala [F (1, 27) =; p <0,0001]). We also showed that lithium treatment modulated the survival and/or maintenance of neurons (immunostaining for NeuN in parietal cortex [F (1, 28) =8,61; p <0,01]; hippocampal area CA1 [F (1, 27) =70,54; p <0,0001]; dentate gyrus [F (1, 27) =75,35; p <0,0001]; subiculum [F (1, 26) =38,67; p <0,0001]; and amygdala [F (1, 27) =72,77; p <0,0001]). Conclusion: The chronic lithium treatment significantly attenuates the pathological progression of AD, suggesting it as a potential therapeutic drug target for modifying AD. The study was funding by: São Paulo Research Foundation (FAPESP; 2021/06378‐1).