Removal of a regulatory gene called LSD1 in adult mice induces changes in gene activity that that look unexpectedly like Alzheimer's disease, scientists have discovered.

Researchers also discovered that LSD1 protein is perturbed in brain samples from humans with Alzheimer's disease and frontotemporal dementia (FTD). Based on their findings in human patients and mice, the research team is proposing LSD1 as a central player in these neurodegenerative diseases and a drug target.

The results are scheduled for publication in Nature Communications.

In the brain, LSD1 (lysine specific histone demethylase 1) maintains silence among genes that are supposed to be turned off. When the researchers engineered mice that have the LSD1 gene snipped out in adulthood, the mice became cognitively impaired and paralyzed. Plenty of neurons were dying in the brains of LSD1-deleted mice, although other organs seemed fine. However, they lacked aggregated proteins in their brains, like those thought to drive Alzheimer's disease and FTD.

"In these mice, we are skipping the aggregated proteins, which are usually thought of as the triggers of dementia, and going straight to the downstream effects," says David Katz, PhD, assistant professor of cell biology at Emory University School of Medicine.

Katz's lab didn't set out to create mice with neurodegenerative disease. LSD1 was known to be critical in early stages of embryonic development, and he and his colleagues were interested in LSD1's role in sperm generation. Graduate students Michael Christopher (Genetics and Molecular Biology) and Dexter Myrick (Neuroscience) are co-first authors of the paper.

When the researchers looked at the patterns of gene activity that were altered in the LSD1-deleted mice, they noticed signs of inflammation and other changes in cell metabolism and signaling. These changes resemble those previously seen in people with Alzheimer's disease and some types of FTD, but not in Parkinson's or ALS.

A more surprising finding came when they examined brain tissue samples from Alzheimer's and FTD patients, in collaboration with Allan Levey, MD, PhD, director of Emory's Alzheimer's Disease Research Center.

"We were amazed to see the accumulation of LSD1 in neurofibrillary tangles in Alzheimer's, and in TDP-43 aggregates in FTD," Levey says. "In both diseases, the LSD1 protein was aberrantly localized in the cytoplasm, along with these pathologies. Since LSD1 is normally localized in the nucleus, these findings provided clues to how it might be linked to the massive yet selective neurodegeneration that we observed in the LSD1-deficient mice, in the same cortical and hippocampal regions known to be vulnerable in these two distinct human neurodegenerative diseases."

For more information go to:

https://www.sciencedaily.com/releases/2017/10/171009084357.htm