Findings Could Pave Way to New Alzheimer’s Treatments

The paper, “Targeting Histone K4 Trimethylation for Treatment of Cognitive and Synaptic Deficits in Mouse Models of Alzheimer’s Disease,” was published on Dec. 9, 2020 in Science Advances.

“By treating Alzheimer’s disease mouse models with a compound to inhibit these enzymes, we were able to normalize gene expression, restore neuronal function, and ameliorate cognitive impairment,” says Yan, SUNY Distinguished Professor of physiology and biophysics.

Alzheimer’s alters the expression of genes in the prefrontal cortex, a key region of the brain controlling cognitive processes and executive functions.

By focusing on gene changes caused by epigenetic processes (those that are not related to changes in DNA sequences) such as aging, Yan and her team were able to reverse elevated levels of harmful genes that cause memory deficits in Alzheimer’s.

The current research extends the work the team reported in 2019 in the journal Brain, in which they were able to reverse the loss or downregulation of some genes beneficial to cognitive function in Alzheimer’s.

In this new paper, the researchers report that it has reversed the upregulation of some genes involved in impairing cognitive function.

Yan explains that transcription of genes is regulated by an important process called histone modification, where histones, the proteins that help package DNA into chromosomes, are modified to make that packaging looser or tighter. 

The nature of the packaging, in turn, controls how genetic material gains access to a cell’s transcriptional machinery, which can result in the activation or suppression of certain genes.

Yan says they found that H3K4me3, a histone modification called histone trimethylation at the amino acid lysine 4, which is linked to the activation of gene transcription, is significantly elevated in the prefrontal cortex of people with Alzheimer’s and mouse models of the disease.

That epigenetic change, she says, is linked to the abnormally high level of histone-modifying enzymes that catalyze the modification known as H3K4me3.

The researchers found that when the Alzheimer’s mouse models were treated with a compound that inhibits those enzymes, they exhibited significantly improved cognitive function.

“This finding points to the potential of histone modifying enzyme-targeted drugs for Alzheimer’s treatment, which may have broad and powerful impact,” Yan explains.

In making that discovery, the team also identified a number of new target genes, including Sgk1 as a top-ranking target gene of the epigenetic alteration in Alzheimer’s. Sgk1 transcription is significantly elevated in the prefrontal cortex of people with Alzheimer’s and in animal models with the disorder.

Yan says they found that abnormal histone methylation at Sgk1 contributes to its elevated expression in Alzheimer’s. 

“Interestingly, the upregulation of Sgk1 is also strongly correlated with the occurrence of cell death in other neurodegenerative diseases, including Parkinson’s disease and amyotrophic lateral sclerosis,” she says.

Sgk1 encodes an enzyme activated by cell stress, which plays a key role in numerous processes, such as regulating ion channels, enzyme activity, gene transcription, hormone release, neuroexcitability and cell death. 

The researchers found that it is highly connected to other altered genes in Alzheimer’s, suggesting it may function as a kind of hub that interacts with many molecular components to control disease progress.

“In this study, we have found that administration of a specific Sgk1 inhibitor significantly reduces the dysregulated form of tau protein that is a pathological hallmark of Alzheimer’s, restores prefrontal cortical synaptic function, and mitigates memory deficits in an Alzheimer’s model,” she explains. 

“These results have identified Sgk1 as a potential key target for therapeutic intervention of Alzheimer’s, which may have specific and precise effects.”

Yan’s co-authors are:

• Qing Cao, PhD, a postdoctoral associate and the first author
• Wei Wang, research scientist
• Jamal B. Williams, a doctoral candidate in the neuroscience program
• Fengwei Yang, bioinformatics specialist
• Zi Jun Wang, PhD, postdoctoral fellow

Funding for the research came from Yan’s grants from the National Institute on Aging of the National Institutes of Health.