Genetic diversity differentially regulates molecular mechanisms of brain aging under normal and pathological conditions

Abstract

AbstractBackgroundGenetically diverse mouse strains have varying life‐spans and varying brain‐aging hallmarks under normal conditions. Studies show that AD mouse models on diverse genomic backgrounds better recapitulate AD‐relevant neuropathological and molecular phenotypes. Mouse models carrying mutant APP and PS1 alleles (APPswe,PS1de9) were generated on eight diverse mouse strains, and significant strain‐specific differences were observed in amyloid deposition, vascular phenotypes, neurodegeneration and transcriptomic signatures. Among those, wild‐derived strains WSB/Eij‐(WSB) and PWK/Phj‐(PWK) gained further attention in AD research. Compared to the APP/PS1 model on standard C57BL/6J‐(B6) mice, WSB.APP/PS1 was associated with elevated neuronal and vascular impairments, whereas, PWK.APP/PS1 was shown to be resilient.MethodWild‐derived strains were originally generated via a backcross strategy, and all PWK.APP/PS1 and WSB.APP/PS1 used in this study were congenic. Cohorts of male and female PWK.APP/PS1 and WSB.APP/PS1 mice and wild‐type controls were aged to 4‐ and 14‐months, and brain hemispheres were processed for RNA‐Seq transcriptomics and neuropathological assessment. In both strains, 14‐months‐old wild‐type mice were compared to 4‐months‐old wild‐type controls to assess brain aging under normal conditions, and 14‐months‐old APP/PS1 mice were compared to 4‐months‐old wild‐type group to assess aging in presence of amyloid pathology (n = 12). Differentially expressed genes were identified and gene set enrichment analysis were performed to determine gene modules and biological pathways associated with brain aging in health and disease.ResultWild‐type aging signatures were mainly strain‐specific with a strong up‐regulation of immune response in WSB, and up‐regulation of metabolic and signaling pathways in PWK. Varying levels of amyloid plaques deposition was observed in the brain of both WSB.APP/PS1 and PWK.APP/PS1 mice. In presence of amyloid, consistent up‐regulation of microglia genes and an elevated immune response was observed. Down‐regulated genes were enriched in synaptic function in WSB, and in pathways of neurodegeneration in PWK.ConclusionThis study suggests that molecular mechanisms of brain aging under normal conditions is modulated by genetic background, and is associated with the response to amyloid pathogenesis. Our findings suggest a potential link between aging‐associated inflammatory state in wild‐type WSB mice and elevated neuronal damage in amyloid pathogenesis, and between preservation of cellular communication in the brain of aged PWK mice and neuronal resilience.