Transcriptional stalling by p16INK4a impairs mitochondrial bioenergetics and cognitive function in Alzheimer’s disease [RNA-seq]

ABSTRACT: CDKN2A/p16INK4a is a canonical marker of cellular senescence and is implicated in aging-related neurodegenerative diseases, including Alzheimer's disease (AD). Yet, how neuronal p16INK4a contributes to neurodegeneration remains unclear, as prior research has largely focused on glial roles . Here, we show that p16INK4a is selectively upregulated in hippocampal granule neurons of AD patient brains and mouse models. Mechanistically, p16INK4a directly binds to GTF2H1, a core subunit of the transcription factor IIH (TFIIH) complex, sterically hindering GTF2H1–RNA polymerase II assembly. This disruption causes genome-wide transcriptional stalling, with preferential downregulation of mitochondrial electron transport chain genes. Notably, p16INK4a overexpression stalls transcription of NDUFB9, a subunit of mitochondrial respiratory complex I, inducing mitochondrial dysfunction and neuronal energy deficits. Hipocampal p16Ink4a overexpression impairs synaptic plasticity and memory in wild-type mice and exacerbates cognitive decline in AD mice, whereas its knockdown restores transcriptional activity, synaptic function, and memory performance. These findings identify a previously unrecognized p16INK4a-mediated cascade linking neuronal senescence to neurodegeneration and establish p16INK4a as an active driver of synaptic dysfunction via direct inhibition of core transcriptional machinery. Targeting the p16INK4a–GTF2H1 interaction may thus offer a therapeutic strategy for AD.

ORGANISM(S): Homo sapiens

PROVIDER: GSE305454 | GEO | 2026/08/19

REPOSITORIES: GEO