Characterization of apathy-like behaviors and their relationship to Aβ pathology in 5xFAD mice.

Abstract

Alzheimer's disease (AD) is a neurodegenerative disease that causes progressive cognitive decline and neuropsychiatric symptoms (NPS) with apathy being highly common. The neurobiological mechanisms of apathy in AD are unclear. This study characterized apathy-like behaviors in 5xFAD mice and their relationship to amyloid-beta (Aβ) pathology in the hippocampus and prefrontal cortex (PFC). We examined apathy-like behavior in male and female 5xFAD mice and wild-type controls at 6, 12, and 16 months of age (n=9-14 per group). Behavioral paradigms included nest building, marble burying, and food burrowing, and we calculated apathy composite scores for each mouse from the results of these three tests. Then, we measured soluble Aβ42 in the hippocampus and PFC of the male and female 5xFAD mice with the highest and lowest apathy composites within each age group by ELISA assay. Finally, we characterized Aβ plaque density and size in the hippocampal CA1 subregion and the PFC using thioflavin-S staining and ImageJ. Three-way, independent sample ANOVAs were conducted to determine the effects of age, gender, and genotype or apathy status on behavioral or biochemical outcomes, respectively. Apathy-like behaviors occurred in 5xFAD mice at all ages (p<.0001 at 6, 12, and 16 months), and these behaviors became more prominent with age. Females displayed more apathetic-like behaviors than males (p<.01). Soluble Aβ42 was substantially greater for 16-month than 6-month 5xFAD mice in the hippocampus (p<.0001) and PFC ( p<.001) and for 12-month than 6-month 5xFAD mice in the hippocampus (p<.01). Higher apathy composites were associated with greater soluble Aβ42 in the PFC and more plaques in the CA1 subregion than lower apathy composites (p<.05 for both). In the PFC, female 5xFAD mice had more plaques than males (p<.01). Plaque density in the CA1 subregion and plaque size in the PFC were greater in 12-month compared to 6-month 5xFAD mice (p<.05 for both). This study demonstrates that 5xFAD mice display apathy-like behaviors starting at 6 months that become significantly worse with age and potentially differ between sexes. Additionally, our study suggests correlations between apathy and soluble and insoluble Aβ pathology that differs by brain region.