Histone demethylase PHF2 regulates inflammatory genes in Alzheimer’s disease

A plethora of factors contribute to cognitive impairment in Alzheimer’s disease (AD), including neuroinflammation, synaptic dysfunction and gene alteration. In search of transcription factors controlling dysregulated genes in AD, we identified that the histone demethylase PHF2 (KDM7C) was a top-ranking candidate. Significant upregulation of PHF2 was found in AD human postmortem tissues, iPSC-derived neurons from AD patients, and a familial AD mouse model (5xFAD). ChIP-seq analysis and quantitative PCR profiling with bidirectional manipulation of Phf2 revealed that Phf2 regulated many genes critically involved in inflammatory pathways and neurodegeneration, including Stat3, Nfkbia, Nfkb2, Tnfrsf1a, Fgfr1, IL6st, Notch2, and Csf1. Knockdown of Phf2 in 5xFAD mice reduced the expression of inflammatory genes, leading to the substantial reduction of microglia/astrocyte activation and the restoration of glutamatergic synaptic function. Behavioral studies showed that Phf2 knockdown in 5xFAD mice significantly improved performance in the Barnes maze test, indicating a mitigation of spatial memory deficits. Our findings have revealed the epigenetic enzyme PHF2 as a regulator of neuroinflammatory processes in AD, linking its activity to both gene expression and cognitive outcomes. It suggests that targeting PHF2 could be a novel therapeutic approach for AD and other brain disorders involving neuroinflammation.