Can the Effects of Alzheimer’s Be Reversed?

Memory loss associated with Alzheimer’s disease (AD) can be restored by inhibiting certain enzymes involved in abnormal gene transcription. That’s according to a new study by University at Buffalo researchers, which they say could pave the way toward new treatments for Alzheimer’s disease.

“By treating AD mouse models with a compound to inhibit these enzymes, we were able to normalize gene expression, restore neuronal function and ameliorate cognitive impairment,” says senior author Zhen Yan, SUNY Distinguished Professor in the Jacobs School of Medicine and Biomedical Sciences at UB.

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

By focusing on genetic changes caused by epigenetic processes (those not related to changes in DNA sequence), such as aging, the researchers were able to reverse elevated levels of harmful genes that cause cognitive impairment in AD. “This is a devastating disease that affects a large population of aged people,” says Yan, who is gratified to have achieved such positive preclinical results from this emerging epigenetics-based approach.

How genes are expressed starts with transcription, which is regulated by a process called histone modification, explains Yan. Histones are proteins that help package DNA into chromosomes. Changes to histones make that packaging looser or tighter, which in turn controls how genetic material gains access to a cell’s transcriptional machinery, activating or suppressing certain genes.

The researchers found that one such histone modification, called H3K4me3, is significantly elevated in the prefrontal cortex of people with AD and in mouse models of the disease.

That elevation is linked to an abnormally high level of histone-modifying enzymes that catalyze H3K4me3, says Yan. When mouse models were treated with a compound that inhibits those enzymes, their cognitive function improved significantly.

In making that discovery, the team also identified a number of target genes that are altered because of the aberrant histone modification in AD. One, Sgk1, was found to be significantly elevated in the prefrontal cortex of people with AD and also highly connected to other altered genes, suggesting that it may function as a kind of hub controlling disease progress. By inhibiting Sgk1 in an AD model, the team was able to ameliorate a pathological hallmark of AD, restore synaptic function in the prefrontal cortex and mitigate memory deficits, suggesting that Sgk1 could one day be a key target for therapeutic intervention.