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bioRxiv · 10.1101/2025.06.04.657838

Genetic modulation of immune gene co-expression in the aged mouse hippocampus by the Apbb1ip locus

Tomkins, J. E.·Methi, A.·Bouland, G.·Doludda, B.·Murphy, K.·Miller, J. A.·Overall, R. W.·Mozhui, K.
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Abstract

Ageing is a major risk factor for many neurodegenerative diseases, and the hippocampus is particularly vulnerable to the effects of ageing. To define the transcriptomic changes related to ageing and the impact of genetic variation, we analysed hippocampal gene expression data generated from a genetically diverse panel of inbred mouse strains belonging to the BXD Family. We applied a combination of differential expression, differential correlation, and weighted gene co-expression network analyses, followed by genetic mapping to delineate age-associated transcriptomic patterns and genetic modulators. This study revealed an upregulation in immune response and microglial genes. We identified a key age-associated co-expression module enriched in immune related genes, and quantitative trait locus mapping of this module uncovered a genetic regulatory locus in which Apbb1ip was the primary candidate gene. Additionally, gene level differential correlation analysis identified a substantial restructuring of the hippocampal transcriptome during ageing. Notably, Ywhab, an important signalling chaperone displayed altered gene expression correlations with >70 genes, between young and aged mice. These results provide novel insights into transcriptional dynamics of hippocampal ageing and identified the immune gene Apbb1ip as a potential modulator of immune response and microglial gene upregulation with implications for neurodegenerative disease pathogenesis. HighlightsO_LIComplementary gene expression analyses indicated an upregulation of immune responses in the ageing hippocampus of a genetically diverse mouse cohort, likely driven by microglia subtypes. C_LIO_LIA systems genetics approach revealed the Apbb1ip locus as a modulator of immune gene co-expression, highlighting a novel candidate regulator of age-associated neuroimmune dynamics. C_LIO_LISignalling chaperone Ywhab gene expression was highly differentially correlated with other transcripts during ageing which may underlie widespread age-associated molecular perturbations in the hippocampus. C_LI

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Tomkins, J. E., Methi, A., Bouland, G., Doludda, B., Murphy, K., Miller, J. A., Overall, R. W., Mozhui, K.. 2025-06-08. Genetic modulation of immune gene co-expression in the aged mouse hippocampus by the Apbb1ip locus. https://doi.org/10.1101/2025.06.04.657838

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