Identification of Histone Methyltransferase SMYD3 and E3 Ligase Fbxo2 as Novel Targets for Treating Cognitive Impairment of Alzheimer's Disease

Jamal Williams

Elevated Smyd3 Leads to Synaptic and Cognitive Deficits in AD via Fbxo2 Mediated NMDAR Degradation.

Elevated Smyd3 Leads to Synaptic and Cognitive Deficits in AD  via Fbxo2 Mediated  NMDAR Degradation.

Graduate Student Project


Imagine if you woke up one morning in a room you didn't recognize, greeted by someone who appeared to be a total stranger. While this may seem like a nightmare to you, more than 5.5 million Americans diagnosed with Alzheimer's disease are susceptible to this fate every day. Individuals afflicted with Alzheimer's disease lose more than just their memories, they are plagued with an overwhelming feeling of bewilderment, and are stripped of their ability to perform the most basic tasks of everyday life.

My name is Jamal Williams, I am a third-year Neuroscience graduate student in the lab of SUNY Distinguished Professor Dr. Zhen Yan. My thesis research is aimed at developing treatments for cognitive impairment associated with Alzheimer's disease.  Researchers have previously discovered that a loss of neurotransmission in the brain is linked to confusion and memory impairment in Alzheimer's patients, yet exactly how this process works is still a mystery. This question is very important, because unless we can identify the key players involved in this process, we cannot develop viable treatments to restore normal cognitive function. Here, I will present the findings of my research, where we have revealed a mechanism linking neurotransmission to cognitive impairment. These findings have allowed us to develop a novel therapeutic strategy to abate the most debilitating facets of Alzheimer's disease.


Cognitive deficits associated with Alzheimer's disease (AD) have been linked to synaptic dysregulation in the prefrontal cortex (PFC), a brain region involved in 'executive' functions, including working memory and decision making. Although, the molecular mechanisms have yet to be fully elucidated. In this study, we explore the hypothesis that aberrant epigenetic modifications are responsible for the dysregulation of genes regulating PFC synaptic functions in AD, contributing to cognitive deficits. Consistently, we have found the permissive histone marker H3K4me3 and its catalyzing enzyme Smyd3 to be significantly elevated in PFC from both AD human postmortem tissues and the AD mouse model P301S, which carries a human mutation for hyperphosphorylated Tau. Behavioral assays indicate that systemic administration of the Smdy3 inhibitor BCI-121 rescues spatial memory and short-term recognition memory deficits in P301S mice. BCI-121 also restores the level of synaptic NMDA receptor expression and transmission in PFC of these mice. ChIP-seq analysis revealed that in PFC of P301S Tau mice, H3K4me3 is significantly enriched at the promoter region of Fbxo2, an E3 ubiquitin ligase responsible for the degradation of NMDA receptor subunit NR1. These data were substantiated by qPCR in both P301S mice and human AD PFC, demonstrating the upregulation of Fbxo2 mRNA. Furthermore, we discovered that selective knockdown of Fbxo2 in PFC of P301S mice significantly ameliorates their memory deficits. These data reveal that the elevated H3K4me3 methyltransferase Smyd3 induces the upregulation of Fbxo2, leading to the abnormal degradation of NMDARs, ultimately causing diminished glutamatergic transmission and cognitive deficits.

See the Full Poster

Click on the file below to see the full poster in your browser. 

Digital Accessibility

The University at Buffalo is committed to ensuring digital accessibility for people with disabilities. We are continually improving the user experience for everyone, and applying the relevant accessibility standards to ensure we provide equal access to all users. If you experience any difficulty in accessing the content or services on this website, or if you have suggestions about improving the user experience, please contact the Experiential Learning Network via email ( or phone (716-645-8177).