Is cognitive decline an inevitable part of aging? And, if so, is there anything we can do to prevent it? Are the neuropathological processes of Alzheimer’s disease (AD) the same or different from a non-AD aging brain?

Although genetic expression studies have shown that there are similarities between normal aging of the brain and AD, such as an increase in expression of genes associated with DNA-damage response and decrease in neuronal genes implicated in synaptic transmission, there are also important differences.

AD is characterized by toxic stimuli (such as B-amyloid) induced blockage of genes that are associated with neural plasticity. So, whereas the aging brain retains its plasticity and is capable of forming new neural pathways and junctions to compensate for losses, the AD brain loses this critical capacity.


Brain REST

In a paper in the highly respected scientific journal, Nature, Lu and his colleagues provide the first detailed investigation of molecular markers in the brain that differentiate between the brains of populations of the young, the aged and those with AD. Briefly, the researchers demonstrated that a protein with the acronym REST (if you insist, it stands for repressor element 1 silencing transcription factor [are you sorry, you asked for it?]) is normally expressed at low concentrations in neurons of young human brains. But in the aging brain, it is expressed at profoundly elevated levels. And in AD? REST levels are markedly reduced, even in patients with mild cognitive impairment, a precursor to full-blown AD.

REST in normal and Alzheimer's brains
REST in the brains of young people (left), switches on in normal aging brains (center) to protect against various stresses, including abnormal proteins associated with neurodegenerative diseases. REST is lost in critical brain regions of people with Alzheimer’s (right). Credit: Yankner Lab


What is the function of REST?

To elucidate the function of REST, the investigators studied the nematode, C. elegans. This primitive organism’s genes have been studied extensively, and although we have diverged from them hundreds of millions of years ago, our genes have their equivalents in the worms.

Single neuron (Photo credit: ZEISS Microscopy (Creative Commons) via PsyPost
Single neuron (Photo credit: ZEISS Microscopy (Creative Commons) via PsyPost

The researchers found that worms deficient in the genes SPR-1, SPR-3 and, particularly, SPR-4 are more sensitive to oxidative stress and have shorter lifespans than the wild type. Those 3 genes evolved from the same ancestral gene as REST and, in fact, SPR-3 and SPR-4 structurally resemble mammalian REST. The researchers found that SPR-4 protects against oxidative stress and B-amyloid toxicity in C. elegans and they found that human REST can functionally substitute for SPR-4 in the worm.

This work is a tour de force. Commenters in Nature wrote that the investigators employed a “dazzling array” of studies to demonstrate the specific role of REST in AD. For the first time, these studies offered a molecular distinction between the normally aging brain and AD. And, the use of worms to identify the function of the REST transcription factor in the human brain is breathtaking in its elegance.


Can these findings translate into treatment?

In the same paper, Lu et al. showed that REST is activated in the aging brain by a cellular signaling pathway called WNT (pronounced wint). Activating WNT should increase the production of REST. So, you may be thinking, can’t we just find some drugs that will activate WNT leading to an increase of rest and neuroprotection of those susceptible to AD?

But not so fast! WNT is also implicated in several cancers. The challenge is to find a way to specifically activate neuronal WNT. Alternatively, further research may be able to find WNT-independent pathways to stimulate REST. Either way, further research is needed.


But, more studies are needed

This is the hallmark of good science. It raises more questions and suggests more hypotheses. And we shouldn’t lose heart at the evolving complexity of REST activation. On the contrary, we should root for it because the more complex a mechanism is, the more points there are for therapeutic intervention.

Featured Photo Credit: Zuerichs Strassen

Dov Michaeli, MD, PhD
Dov Michaeli, MD, PhD loves to write about the brain and human behavior as well as translate complicated basic science concepts into entertainment for the rest of us. He was a professor at the University of California San Francisco before leaving to enter the world of biotech. He served as the Chief Medical Officer of biotech companies, including Aphton Corporation. He also founded and served as the CEO of Madah Medica, an early stage biotech company developing products to improve post-surgical pain control. He is now retired and enjoys working out, following the stock market, travelling the world, and, of course, writing for TDWI.



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