Journal Article

DZNE-2026-00417

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Lifestyle shapes preclinical social and microglial deficits in an Alzheimer's disease mouse model.

Ehret, F. (First author)DZNE* ; Doludda, B.DZNE* ; Liu, H.DZNE* ; Nexhipi, S. ; Huang, H. ; Rost, F. ; Overall, R.DZNE* ; Barde, W.DZNE* ; Rünker, A. E.DZNE* ; Sieweke, M. ; Dahl, A. ; Schmidt, M. H. H. ; Kempermann, G. (Last author)DZNE*

2026
Springer Nature [London]

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Please use a persistent id in citations: doi:10.1038/s41380-025-03368-4

Abstract: Alzheimer's disease has a long preclinical phase, during which no overt signs of the manifest disease are present, but subtle, usually non-specific changes are already detectable. Emerging early biomarkers underscore the importance of this phase for preventive measures including lifestyle interventions. As a reductionistic model for lifestyle factors, we used a novel enrichment paradigm in which AppNL-G-F knock-in mice were continuously tracked until 7 months of age. Despite minimal plaque burden and no memory impairment at that age, there were early and progressive deficits in social parameters - such as following behavior, social interaction, and exploration - suggesting preclinical behavioral vulnerability. Altered correlations between adult neurogenesis and social parameters linked neural plasticity to preclinical behavior. Plasma profiling at 3 months identified early systemic shifts in markers of inflammation and apoptosis that predicted later cortical pathology. We found increased microglia coverage in more socially active animals. More actively exploring controls, but not AppNL-G-F mice, exhibited more ramified and less amoeboid microglia, suggesting that AD pathology impairs immune surveillance at a very early stage. Single-cell RNA sequencing of hippocampal microglia revealed that enrichment dampened interferon-responsive microglia, which typically increase as amyloidosis advances. A shifted immune response was also measured by reduced transcripts related to antigen processing and presentation and by increased chemokine signaling. Our study demonstrates that the preclinical phase of AD is not silent, but even in a reductionistic knock-in model characterized by early interwoven preclinical changes in multiple domains, including brain plasticity, behavioral trajectories, sociality and immunity.

Keyword(s): Animals (MeSH) ; Alzheimer Disease: metabolism (MeSH) ; Alzheimer Disease: physiopathology (MeSH) ; Alzheimer Disease: pathology (MeSH) ; Microglia: metabolism (MeSH) ; Mice (MeSH) ; Disease Models, Animal (MeSH) ; Mice, Transgenic (MeSH) ; Male (MeSH) ; Social Behavior (MeSH) ; Life Style (MeSH) ; Hippocampus: metabolism (MeSH) ; Amyloid beta-Protein Precursor: metabolism (MeSH) ; Amyloid beta-Protein Precursor: genetics (MeSH) ; Behavior, Animal: physiology (MeSH) ; Mice, Inbred C57BL (MeSH) ; Neuronal Plasticity: physiology (MeSH) ; Brain: metabolism (MeSH) ; Neurogenesis: physiology (MeSH) ; Amyloid beta-Peptides: metabolism (MeSH) ; Female (MeSH) ; Amyloid beta-Protein Precursor ; Amyloid beta-Peptides

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Contributing Institute(s):

1. Adult Neurogenesis (AG Kempermann)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2026

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Springer ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 10 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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