Pre-symptomatic reduction of individuality in the App^NL-F knock-in model of Alzheimer’s disease

Abstract

While one third of the risk for Alzheimer's disease (AD) is explained by environment and lifestyle, AD pathology also affects individual lifestyle, possibly long before clinical manifestation of dementia. To study this hidden disease effect with its potentially large impact on coping with AD, we examined in mice how the App NL-F/NL-F (NL-F) knock-in mutation affects the pre-symptomatic response to environmental enrichment (ENR). We assessed the emergence of inter-individual phenotypic variation while both genetic background and the shared environment were held constant, thereby isolating the contribution of individual behavior ('non-shared environment'). After 4 months of ENR, in NL-F both mean and variability of plasma ApoE were increased, suggesting a pre-symptomatic variation in pathogenic processes. Roaming entropy (RE) as a measure of behavioral activity was continuously assessed with radiofrequency identification (RFID) technology and revealed reduced habituation and variance in NL-F compared to controls. Intra-individual variation decreased but behavioral predictability and stability were reduced in NL-F. Seven months after discontinuation of ENR we found no difference in plaque size and number, but ENR increased variance in hippocampal plaque counts in NL-F. A reactive increase in adult hippocampal neurogenesis in NL-F, known from other models, was normalized by ENR. Our data suggest that, while NL-F has early effects on individual behavioral patterns in response to ENR, there are lasting effects at the level of cellular plasticity even after discontinuation of ENR. Hence, early behavior matters for maintaining individual behavioral trajectories and brain plasticity even under maximally constraint conditions.

Exploring social modulation: Microglia as a key mediator of individual immune response, plasticity and pathology in App-NL-G-F mouse model of Alzheimer’s disease

“…This analysis aimed to calculate the individual exploration rate using mean RE, to compare behavioral trajectories of NL-G-F and NL mice. While the majority of NL mice habituate to the environment over time, as demonstrated previously 4 , NL-G-F mice exhibit deficits in habituation behavior as time progresses (Fig 1B , C). In addition to these reduced adaptability traits in NL-G-F mice, social analysis reveals differences in their following behavior (Fig.…”

“…While some studies have hinted at a link between loneliness and increased amyloid burden in cognitively normal older adults, there is a significant gap in our understanding of social deficits and social networks in individuals during the preclinical stages of AD. Although research in various AD mouse models has shown that social deficits and anxiety can manifest in middle-aged and older mice [22][23][24] , it's crucial to emphasize that very few studies, including our prior work, have specifically addressed altered behaviors, such as changes in exploration, rearing, and social memory, in mice exhibiting AD-like characteristics during the pre-symptomatic stages 4,23,25,26 . In our current study we were able delved deeper into the aspect of social structure and following behavior over time due large cohort and longitudinal analysis over 5 1/2 months.…”

“…Compositional analysis (Fig. 5B) unveiled a reduction in homeostatic phenotypes (0-1) in NL-G-F mice, accompanied by a shift towards DAM activation stages (2,4).…”

“…We previously tackled certain aspects of behavioral intervention and identified abnormalities in a knockin animal model of AD 4 . Specifically, we observed deficits in habituation to an environment during presymptomatic stages, coupled with reduced stability in behavioral traits.…”

“…However, it is worth noting that within this initial study we refrained from further analyses of social interaction. This aspect became more relevant with the discovery that mice appeared prone to become disoriented and loose behavioral flexibility 4 , which possibly influence their social interaction. Social interaction contributes to a more robust cognitive reserve 5, 6 , which may act as a protective factor against the onset and progression of neurodegenerative diseases.…”