Basic Science and Pathogenesis.

Background: In Alzheimer's disease (AD) the fact that neuropsychiatric symptoms can predate the onset of cognitive symptoms suggests that greater focus on the non-cognitive behavioral changes in earlier life could be an opportunity to investigate 'latent' mild behavioral impairment (MBI) as a possible diagnostic strategy for preclinical AD.

Method: We used 1- and 6-month-old 3xTg-AD male mice and age-matched wild-type animals (CEUA-ICB/USP: 127/2015). Two batteries of behavioral tests were performed: (1) open field test (OFT), novel object recognition test (NORT), and rotarod test; (2) elevated zero maze test (EZMT), forced swim test (FST), and sucrose preference test (SPT). The immunohistochemistry method was performed to analyze amyloid-β (Aβ) accumulation (6E10) in areas of the brain. Statistical analysis was performed through two-way ANOVA followed by a Bonferroni post-hoc test and unpaired t-test (IBM SPSS Statistics® software 23). We considered statistically significant p<0.05.

Result: In both OFT (F = 22.92, p<0.001) and EZMT (F = 41.72, p<0.001), a rise in anxiety-related responses was detected in 3xTg-AD versus Controls mice from an early age. We also detected depressive-like behavior in 1- and 6-month-old 3xTg-AD evaluated by FST (F = 40.88, p<0.001). In SPT, 6-month-old 3xTg-AD presented a decrease in sucrose preference versus Controls of the same age and versus 1-month-old 3xTg-AD (F = 8.77, p = 0.006), suggesting signs of anhedonia at a later age. NORT was applied to evaluate cognition, which showed 6-month-old 3xTg-AD mice were not able to discriminate the novel from the familiar object in short- (F = 132.14, p<0.001) and long-term memory (F = 275.86, p<0.001) versus Controls. The immunoreactivity analysis showed that 6-month-old 3xTg-AD exhibited a significant increase in Aβ versus 1-month-old 3xTg-AD (parietal cortex, p<0.001; hippocampal CA1, p<0.001; dentate gyrus, p<0.001), justifying occurrence of memory impairment at a late age. When analyzing the amygdala, 1- and 6-month-old 3xTg-AD showed similar Aβ immunoreactivity (p = 0.2), suggesting that premature accumulation of Aβ in amygdala can be contributed to dysfunction in emotional responses.

Conclusion: Taken together, we propose that anxiety-like and depressive-like behaviors can be detected at an early age in 3xTg-AD mice as a 'latent' MBI syndrome, positioning it as a possible diagnostic strategy for preclinical AD.