Epigenetic mechanisms of selective vulnerability of entorhinal PV neurons in aging and AD

Alzheimer’s disease (AD) is characterized by the selective vulnerability of specific brain regions and neuronal populations. The entorhinal cortex (EC) is one of the most vulnerable brain regions during the early stage of AD. Neurons in the EC, particularly the fast-spiking, parvalbumin (PV)-positive GABAergic neurons, are vulnerable to degeneration in AD. The loss of PV neurons strongly correlates with AD pathology and cognitive impairment. However, the molecular mechanisms underlying the selective vulnerability of EC PV neurons during aging and AD remain unknown. Epigenetic modifications play an important role in neuronal degeneration by regulating gene expression patterns. The enhancer of zeste homolog-2 (EZH2), a histone methyltransferase and an enzymatic catalytic subunit of PRC2, can alter gene expression by catalyzing H3K27 trimethylation (H3K27me3), a repressive marker, or functioning as a transcriptional activator. Our preliminary data demonstrate that both EZH2 and H3K27me3 are downregulated in the EC of AD mouse models. Moreover, EZH2 overexpression in neurons mitigates cognitive impairment in aged mice. We hypothesize that EZH2 downregulation is a key driver of entorhinal PV neuron vulnerability in aging and AD progression, contributing to neuropathological changes and cognitive decline by altering cell-specific transcriptomic profiles. We will determine 1) whether EZH2 in EC PV neurons is a critical determinant of neuronal and cognitive dysfunction during aging, 2) whether EZH2 protect PV neurons against Aβ and tau pathology and cognitive deficits in APP and tauopathy mouse models, and 3) what molecular pathways targeted by EZH2 drive EC PV neuron dysfunction and degeneration. Project Number: 1R01AG099139-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Yun Lei | Institution: AUGUSTA UNIVERSITY, AUGUSTA, GA | Award Amount: $542,699 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 AN-Q (55)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11301563