Memory, Circadian Rhythm, and Goal-Directed Behavior in an ApoE4/APP Mouse Model of Alzheimer’s Disease




Graybeal, John

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While previously developed models of Alzheimer’s Disease (AD) have led to significant insights into the mechanisms of AD pathology, the majority of these models have a collective limitation. They utilize an early-onset mutation to induce pathology, which is representative of only about five percent of the AD population. We have developed a novel mouse model that builds on the Westaway mouse, which contains a single copy of doubly mutated human amyloid precursor protein (hAPP) gene. In addition to this doubly mutated hAPP gene, our model incorporates the strongest genetic risk factor for late-onset AD, the Apolipoprotein E (ApoE) ε4 allele. This study aimed to establish a behavioral profile for the ε4/hAPP mouse and to demonstrate its ability to model the changes seen in human AD pathology, especially in individuals with the ApoE ε4 allele. This study examined disruption to medial temporal lobe function, disruption to circadian rhythm function, and impairments in goal-directed behaviors, by comparing them to the traditional hAPP model on which they were based. To this end, the Novel Object Recognition (NOR) and Morris Water Maze (MWM) tests were employed to examine memory deficits. Circadian rhythm disruption was evaluated by tracking wheel-running behavior with Clocklab software (Colbourne Instruments). Nest construction was also evaluated. Behavioral outcomes were then correlated with key markers of inflammation, TNF-α and IL-1β. Differences in MWM and NOR performance were non-significant, except during the twenty-four hour probe trial when ε4/hAPP mice showed a lower average distance from the platform (Gallagher measure). Compared to wild-type (WT) controls, ε4/hAPP mice showed significantly more frequent (p=.002) but shorter (p=.014) bouts of activity while displaying non-significant differences in average activity levels, indicating disruption to the regular circadian patterns seen in WT controls. Both ε4/hAPP mice and hAPP mice showed impairments in nest-building behavior. Across all statistically different behavioral measures, ε4/hAPP mice outperformed hAPP mice, which were significantly different from WT mice on many measures. This trend was consistent with the pattern of significant differences observed in IL-1β levels. While both transgenic models showed increased inflammation compared to WT controls, ε4/hAPP mice showed less inflammation than hAPP mice. In this study, the ε4 allele provided beneficial effects, which we believe reflects the young age at which the animals were tested.



Late-onset Alzheimer's, Circadian Rhythm, Transgenic mice, Nest building, Inflammation, ApoE4