Can we differentiate between the aging brain and Alzheimers?
A few weeks ago I was interviewed by Dr. Pat Salber on her internet radio program, The Doctor Weighs In (on the Radio). One of the topics we discussed was whether cognitive decline is an inevitable part of aging – and whether there was anything we could do to prevent it.
Whenever this subject is discussed, the conversation invariably turns to Alzheimer’s disease (AD) and whether this dread disease can be prevented, or at least ameliorated? The short answer is that the root cause of memory loss of normal aging is different from that of AD. Thus far, we don’t even know the molecular mechanism of the AD, let alone the means to stop it.
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.
For instance, toxic stimuli are characteristic of AD-related neuro-degeneration induced blockage of genes associated with neural plasticity. This was the basis for my answer in the interview that normal aging and AD are fundamentally different. The aging brain retains its plasticity and is capable of forming new neural pathways and junctions to compensate for any losses. The AD brain loses this critical capacity.
Why did neuronal genes lose their capacity to protect the aging brain?
Improtantly, these studies did not answer a crucial question - why did those genes lose their capacity to protect the aging brain?
In a paper in Nature, Lu and his co-workers 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 demonstrate 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.
What is the function of REST? For that, the investigators studied the nematode worm C. elegans. This primitive organism’s genes have been studied extensively, and although we have diverged from worms hundreds of millions years ago, our genes have their equivalents in the worms. They found that worms deficient in the genes spr-1, spr-3 and spr-4 are more sensitive to oxidative stress and have shorter lifespan than the wild type. And the clincher: those 3 genes evolved from the same ancestral gene as REST. Therefore, REST’s action confers resistance to neurotoxic stress, and specifically, oxidative stress.
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 human brain is breathtaking in its elegance.
Can the results of the studies be used therapeutically?
The inevitable question on everybody’s mind: can the results of these studies be used therapeutically? The answer is “probably. ” In the same paper, Lu et al showed that REST is activated by a cellular signaling pathway called WNT (pronounced wint). Activating WNT should increase the production of REST.
But not so fast, though; WNT is also implicated in several cancers. The challenge is to find a way to specifically activate neuronal WNT. Alternatively, further research could find WNT-independent pathways to stimulate REST. Either way, further research is 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.