DNA methylation and Alzheimer’ Disease & A selective inhibitor of histone demethylase LSD1

Last weekend, we visited a nursing home for the elderly. Most of them are suffering from Alzheimer’s disease (AD), which make them forget a lot of things, even their relatives and friends. As is known, Alzheimer’s disease is one of neurodegenerative diseases, which involves multiple pathologic processes and affect an estimated 1 in 10 people over age 65. Alzheimer’s is predicted to affect 1 in 85 people globally by 2050.

According to previous studies, mutations in key AD genes have been identified to cause the development of AD, while the exact cause of those cases is generally unknown. Recently, I is shown that alterations in epigenetic processes GF 109203X are also involved in the pathophysiology of AD. Of which, one of several epigenetic markers altered in AD brain is 5-methylcytosine [5mC], which is involved in many important biological processes such as gene imprinting, chromatin structure, and X-chromosome inactivation. In addition, 5mC also play important roles in aging, cellular differentiation, neuronal development, learning and memory. During the development of AD, low levels of 5-hydroxymethylcytosine (5hmC) are found in most tissues including liver, lung, and heart, while high levels are in brain.

Therefore, increased levels of DNA modifications in the brain may be a biomarker of AD and the related DNA methylation inhibitors may be the potential way for AD therap

Lysine-speci?c demethylase 1 (LSD1), is responsible for oxidatively removing one or two methyl groups from Lys4 of histone H3 (H3K4). It has been reported that LSD1 levels are often increased in various cancers, including prostate, non-small cell lung, and ER-negative breast cancer. A variety of tumor suppressors that have been shown to be silenced in cancer by epigenetic mechanisms could theoretically be restarted by LSD1 inhibitors. The mechanism of LSD1 action is that using molecular oxygen as a co-substrate and generates hydrogen peroxide and formaldehyde as byproducts.

Previous work showed that the antidepressant MAO inhibitor phenelzine is considerably more potent than tranylcypromine as an LSD1 inhibitor. In this study, a series of phenelzine analogues informed by the general concept derived from tranylcypromine studies are generated. HDAC inhibition has previously been reported to protect against oxidative stress in neurons subjected to homocysteic acid (HCA) treatment, which induces glutathione depletion.

In summary, this work find a potent and selective LSD1 inhibitor, bizine, derived from the MAO inhibitor phenelzine. Structure-activity relationships demonstrate the vital Nepicastat roles of the hydrazine functionality, the secondary amide linker, and the second aryl group in achieving potent LSD1 inhibition. A promising direction is the application of LSD1 inhibition in neuroprotection against oxidative stress. Bizine should be a useful probe in the evaluation of LSD1’s demethylase activity in physiologic and pathophysiologic conditions.