What question did this study set out to answer?

The aim is to examine the role of p16Ink4a in spatial cognition and gene expression in adult mice, particularly under amyloidogenic conditions.

February 28, 2026Open Access

Cdkn2a/p16Ink4a loss impairs Spatial memory independently of Alzheimer’s-associated genetic pathways in young adult mice

Puntos clave

The aim is to examine the role of p16Ink4a in spatial cognition and gene expression in adult mice, particularly under amyloidogenic conditions.
Investigated spatial learning using the Morris Water Maze (MWM)
Analyzed hippocampal gene expression through RNA sequencing
Compared control mice with p16Ink4a knockout and amyloid pathology models
Conducted differential gene expression and gene set enrichment analysis (GSEA)
Loss of p16Ink4a led to mild, short-lived spatial learning deficits
Transcriptomic analysis showed upregulation of metabolic pathways and downregulation of synaptic genes
AppNL−G−F mice demonstrated strong immune activation, contrasting with the p16Ink4aKO
Double mutants revealed complex transcriptional interactions without exacerbating amyloid pathology effects

Resumen

The cyclin-dependent kinase inhibitor CDKN2A/p16INK4A (p16INK4A) is a central regulator of cellular senescence, widely studied in ageing and cancer. Although its expression increases with age and disease, its role in the adult brain remains poorly defined. Recent evidence suggests a possible contribution to neuroinflammation and cognitive decline in Alzheimer’s disease (AD), but underlying mechanisms are unclear. We investigated the functional impact of p16Ink4a inactivation on spatial cognition and hippocampal gene expression in adult mice under normal and amyloidogenic conditions using the AppNL−G−F AD model. Spatial learning and memory were assessed using the Morris Water Maze (MWM). Hippocampal transcriptomes from control, p16INK4Aknockout (p16Ink4aKO), AppNL−G−F, and double mutant mice were analysed by RNA sequencing. We performed differential gene expression analysis, gene set enrichment analysis (GSEA), and interaction modelling to assess the molecular consequences of p16Ink4a loss alone and in combination with amyloid pathology. Loss of p16Ink4a resulted in modest and short-lasting alterations in spatial learning and early memory retrieval, without exacerbating early deficits in AppNL−G−F mice. Transcriptomic analysis indicated that p16Ink4aKO upregulated metabolic, mitochondrial, and translational pathways, while downregulating synaptic and cytoskeletal genes. In contrast, AppNL−G−F mice displayed strong immune activation. The double mutants showed additive transcriptional changes, yet GSEA indicated non-linear interactions in synaptic and immune-related pathways. Unexpectedly, p16Ink4a deletion alone was associated with enrichment of senescence-related signatures. Constitutive p16Ink4a loss shows modest effects on spatial memory and broad hippocampal transcriptomic changes, independently of amyloid pathology. These findings point to possible non-canonical roles for p16Ink4a in neuronal homeostasis and emphasise the need for temporally controlled models to better dissect the brain-specific functions of senescence regulators in ageing and neurodegeneration.

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