Lifestyle shapes premorbid social and microglial deficits in an Alzheimer’s disease mouse model
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ABSTRACT: In this study we used a knock-in mouse model of Alzheimer's disease, App-NL-G-F mice. As a reductionistic model for lifestyle factors, we used a novel enrichment (ENR) paradigm in which App-NL-G-F mice and controls (App-NL) were continuously tracked until 7 months of age. In comparision mice from both genotypes were housed in standard (STD) cages to identify the effect of social housing and exploratory activity. Despite minimal plaque burden and no memory impairment, these mice displayed progressive deficits in social parameters — such as following behavior, social interaction, and exploration – suggesting early behavioral vulnerability. Altered correlations between adult neurogenesis and social parameters emerged by 7 months, linking neural plasticity to premorbid behavior. Morphological analysis of microglia indicated increased microglia coverage in more socially active animals. Exploratory active controls, but not App-NL-G-F mice, exhibit more ramified and less amoeboid microglia, suggesting that this relationship is disturbed by pathology. At the end of the experiments randomly selected animals were processed for single-cell RNA sequencing of hippocampal microglia. In App-NL-G-F mice enrichment dampened interferon-responsive microglia, which typically increase as amyloidosis advances. A shifted immune response was measured by reduced transcription of genes related to antigen processing and presentation and by increased chemokine signaling. Our study demonstrates interwoven preclinical alterations in an AD mouse model involving multiple domains, including brain, behavior and immune system, and, thus, provides experimental access to the complex interplay between pathology and behavior (at premorbid stages of Alzheimer’s disease).
ORGANISM(S): Mus musculus
PROVIDER: GSE301217 | GEO | 2025/07/01
REPOSITORIES: GEO
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