Yu Chen, Andrew R Ouellette, Yiding Cao, Jigang Zhang, Catherine C Kaczorowski
Aging and cognitive decline exhibited differential transcriptional signatures. Aging-related changes were modest and cell-type specific, with early responses in excitatory neurons followed by increased glial remodeling. Conversely, cognitive decline was associated with widespread transcriptional alterations predominantly in excitatory neurons, enriched for proteostasis and glutathione/redox pathways.
INTRODUCTION: Genetic factors contribute to variability in age-related cognitive decline, yet the molecular mechanisms underlying cognitive resilience remain poorly understood.
METHODS: We performed single-nucleus RNA sequencing on hippocampal tissue from 107 genetically diverse Collaborative Cross mice across three ages (6, 12, and 18 months) and both sexes. Contextual fear memory was used as a continuous measure of cognitive function. Pseudobulk differential expression analyses identified transcriptional changes associated with aging and cognitive decline.
RESULTS: Aging and cognitive decline exhibited differential transcriptional signatures. Aging-related changes were modest and cell-type specific, with early responses in excitatory neurons followed by increased glial remodeling. Conversely, cognitive decline was associated with widespread transcriptional alterations predominantly in excitatory neurons, enriched for proteostasis and glutathione/redox pathways.
DISCUSSION: These findings indicate that cognitive decline is not simply a consequence of aging but reflects distinct molecular processes in excitatory neurons. Proteostasis and redox pathways may represent conserved mechanisms supporting cognitive resilience.