Basic Science and Pathogenesis

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.

We tested lithium carbonate treatment (1.0g Li₂CO₃/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.

two-way ANOVA followed by Bonferroni post-hoc test and unpaired t-test; statistically significant p <0.05.

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]).

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).