REST Regulates Neuronal Genes in the Aging Brain, Is Absent in AD

A new study by a team of researchers led by Bruce A. Yankner, MD, PhD, Professor of Genetics and Neurology, Harvard Medical School, Director of the Harvard Neurodegeneration Training Program, and Codirector of the Paul F. Glenn Laboratories for the Molecular Biology of Aging, has found that a gene regulating protein known as REST (repressor element 1-silencing transcription factor) is involved in protecting the aging brain by reducing oxidative stress, but its absence in old age signals brain disorders, especially Alzheimer’s disease (AD) and potentially other types of dementia (Lu T, et al. Nature. 2014;507:448-454).

The team found that REST confers neuroprotective qualities during aging: it is active during fetal development and then is reactivated during the aging process, reducing oxidative stress and protecting neurons in the brain from stresses, including the various proteins that have been implicated in AD. Furthermore, REST is diminished in early AD and is absent in the brain of patients with full-fledged AD.

REST has been known as a “repressor of neuronal genes during embryonic development that is downregulated once terminal neuronal differentiation has occurred,” the authors wrote. What this new study shows is that “REST is induced in the ageing human brain and regulates a network of genes that mediate cell death, stress resistance and AD pathology. This gene network becomes dysregulated at early stages of AD pathology.” Furthermore, REST “plays a role as a neuroprotective modulator, in part by repressing genes that promote cell death and the pathology of AD,” they note.

REST activates genes that promote neuronal response to stress, a natural mechanism developed to preserve brain function and brain well-being.

However, according to Dr Yankner and colleagues, “REST is induced in the ageing brain and declines in AD. Transcriptional profiling has demonstrated significant changes in the expression of neuronal genes in the prefrontal cortex of the ageing humans.”

Therefore, testing people for the level of REST in their brain could determine who is likely to develop AD.

“One very positive, optimistic note from this study is that it suggests that dementia can be resisted by some people, and it provides the first molecular inkling of how that might occur, “ Dr Yankner said in an interview with the Boston Globe.

Developing a test that shows who has low levels of REST may be the first step to developing preventive therapies for AD.