Mild Behavioral Impairment and Amyloid-Β Accumulation in the Amygdala Precede Cognitive Decline in Juvenile Male 3xtg-Ad Mice

Neuropsychiatric symptoms (NPS) affect nearly all individuals with Alzheimer's disease (AD). Recent studies show that NPS may also occur at pre-dementia stages referred to as mild behavioral impairment (MBI). Here, we assess the manifestations of MBI-like behaviors in an animal model of AD at the early stages of the disease and their relationship with age-dependent amyloid-β (Aβ) accumulation. We used a behavioral test battery to ascertain differences in cognitive and non-cognitive behaviors in 1- and 6-month-old male triple-transgenic AD mice model (3xTg-AD mice), and determined the immunoreactivity to Aβ in distinct brain regions to investigate a possible overlap of Aβ pathology with abnormal behavioral phenotypes in juvenile and adult mice. Neurobehavioural abnormalities suggestive of increased anxiety and depression-like behaviors were detected in juvenile 3xTgAD mice without any evidence of memory impairment at 1 month of age; these changes were accompanied by Aβ accumulation in the amygdala. In adult mice, both short- and long-term recognition memory was impaired, coinciding with increased Aβ levels in limbic and neocortical structures. These results demonstrate that anxiety- and depression-like behaviors may be observed at early developmental stages in 3xTg-AD mice, preceding the onset of cognitive decline, which could represent an animal model for the study of ​MBI-like behaviors. We further show that these findings may be temporally associated with early Aβ accumulation in the amygdala.