Basic Science and Pathogenesis.

Background: Nearly all individuals with Alzheimer's disease (AD) develop neuropsychiatric symptoms (NPS). Lithium is a mood-stabilizer and is efficient in reducing disruptive behaviors in bipolar-disorder; this characteristic could be an opportunity to investigate the use of lithium in treating behavioral changes in AD.

Method: We tested lithium carbonate treatment in 3xTg-AD and age-matched Wild-type male mice (CEUA/PROCESS: 1605/2020; 4127240122). The drug was administered ad libitum via lithium-supplemented chow (1.0g LiCO/kg of chow; 12-weeks) from 9- to 12-month-old. 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) in areas of the brain. Statistical analysis was performed using two-way ANOVA followed by Bonferroni post-hoc test and unpaired t-test (IBM_SPSS Statistics® software 23). We considered statistically significant p<0.05.

Result: Our results demonstrated that lithium had a significant rescue/prevention effect on anxiety- and depression-related behaviors in AD. In both OFT (F = 37.15; p<0.001) and EZMT (F = 19.44; p<0.001), a suppression in anxiety-related responses was detected in 3xTg-AD+Lithium mice versus 3xTg-AD. Similar results were found in TST (F = 11.70; p<0.01) and FST (F = 7.96; p<0.01) with reduction of depressive-related behavior. In SPT (F = 17.86; p<0.001), 3xTg-AD+Lithium mice presented an increase in sucrose preference versus 3xTg-AD, suggesting benefice effects of lithium on anhedonia signs detected in AD. In NORT, 3xTg-AD+Lithium mice demonstrated greater index in recognition memory parameter versus 3xTg-AD, suggesting prevention of short- (F = 8.37; p<0.01) and long-term memory (F = 7.99; p<0.01) in AD. We also reported reduction of nearly 50% in Aβ immunoreactivity in areas such as parietal cortex (F = 571.90; p<0.001), CA1 (F = 357.28; p<0.001), dentate gyrus (F = 417.74; p<0.001), subiculum (F = 7073.19; p<0.001), entorhinal cortex (F = 1562.86; p<0.001), and amygdala (F = 419.79; p<0.001), in 3xTg-AD+Lithium mice versus 3xtg-AD; suggesting the neuroprotective action of lithium, which partially explains the positive cognitive and non-cognitive behavioral changes observed with chronic lithium treatment.

Conclusion: The efficacy of a low-dose lithium treatment in improving cognitive loss and NPS suggest it as therapeutic potential to treat AD.