August 28, 2006
Boost Of Brain Enzyme Restores Memory In Alzheimers Mice

Boosting the enzyme ubiquitin C-terminal hydrolase L1 (Uch-L1) in mouse brains suffering from Alzheimer's restored the ability of the mice to form new memories.

NEW YORK August 24, 2006 -- Researchers at Columbia University Medical Center have successfully restored normal memory and synaptic function in mice suffering from Alzheimer's disease. The study was published today on the website of the journal Cell.

Scientists at Columbia's Taub Institute for Research on Alzheimer's Disease and the Aging Brain have identified an enzyme that is required for normal cognition but that is impaired in a mouse model of Alzheimer's. They discovered that mice regained the ability to form new memories when the enzyme's function was elevated.

The research suggests that boosting the function of this enzyme, known as ubiquitin C-terminal hydrolase L1 (Uch-L1), may provide a promising strategy for battling Alzheimer's disease, and perhaps reversing its effects.

In the new study, the Columbia researchers discovered that the enzyme Uch-L1 is part of a molecular network that controls a memory molecule called CREB, which is inhibited by amyloid beta proteins in people with Alzheimer's. By increasing Uch-L1 levels in mice that had Alzheimer's, they were able to improve the animals' ability to create new memories.

"Because the amyloid beta proteins that cause Alzheimer's may play a normal, important physiological role in the body, we can't destroy them as a therapy," explained Ottavio Arancio, M.D., Ph.D., Assistant Professor of Pathology at Columbia University Medical Center and co-principal investigator of the study with Michael Shelanski, MD, Ph.D., Chairman of the Department of Pathology at the Columbia University College of Physicians and Surgeons. "What makes this newly discovered enzyme exciting as a potentially effective therapy is that it restores memory without destroying amyloid beta proteins."

We'll have effective cures for Alzheimer's before cancer becomes totally curable. Alzheimer's is an easier problem.

The Uch-L1 prevents a harmful consequence of too much beta amylod.

"While amyloid beta is certainly a key player in Alzheimer's disease--and efforts to reduce it remain a worthy goal--our results show that, even in the presence of the plaque, damage to memory can be reversed."

The findings suggest that neurons' protein-ridding machinery, the so-called ubiquitin/proteasomal pathway, may play an important early role in the pathogenesis of Alzheimer's disease, he added.

Ubiquitin is a "tag" that marks proteins for destruction by the cellular "garbage disposal" known as the proteasome, Shelanski explained. Uch-L1 acts as the proteasome's "gatekeeper," he added. Before proteins can be eliminated by the proteasome, Uch-L1 must remove their ubiquitin tag.

Earlier studies found that the brains of Alzheimer's disease patients show an accumulation of ubiquitin-tagged proteins, suggesting some defect of the protein degradation machinery, the researchers noted. Studies of the brains of humans with Alzheimer's after death found evidence that the proteasome remained intact but largely unable to degrade proteins.

Interestingly, Uch-L1--a protein found almost exclusively in nerve cells--was also found at reduced levels in the Alzheimer's brain. Unpublished studies by Shelanski's group found that cells treated with Aß exhibited a rapid drop in Uch-L1, he said.

Uch-L1 doesn't sound like it stops the underlying cause of Alzheimer's. But if boosting it delays Alzheimer's disease progression drugs that boost Uch-L1 will buy Alzheimer's sufferers valuable time while treatments are devised that fix the underlying causes of the disease.

We need gene therapies that will rejuvenate the mechanisms which brain cells use to break down and remove proteins that are no longer needed. The aging of junk removal mechanisms probably leads to accumulation of junk in and around cells. That junk causes damage to cells and interferes with their operations and communications.

Development of treatments to improve intracellular and extracellular junk removal are two of the rejuvenation Strategies for Engineered Negligible Senescence (SENS).

Share |      Randall Parker, 2006 August 28 10:54 PM  Brain Alzheimers Disease

Allan L said at August 30, 2006 2:47 AM:

A very recent study claimed that tetrahydrocannabinol (THC), the active ingredient in marijuana, completely prevented formation of amyloid plaque. The article I read made the study seem legitimate, though I am ignorant of details, such as how much is enough.

In the FuturePundit article, Dr. Arancio claims that plaque causes Alzheimer's. The other article said that plaque could be cause or effect, and that its role in Alzheimer's is unknown thereby making THC's efficacy unknown. So if Dr. Arancio is correct that plaque does cause Alzheimer's, then THC can cure Alzheimer's!

Given that the brain's volume is either constant or shrinking, the presence of plaque indicates the displacement and absence of whatever was there before it, and that plaque is bad, even if it is not the cause.

How does the saying go? An ounce of prevention ... costs about $200.

Nick said at August 30, 2006 8:50 AM:

As I read the article, it seems to be saying that this new treatment restores the garbage removal function. That sounds pretty close to a cure.

Randall Parker said at August 30, 2006 5:21 PM:

Allan L,

I did a post on the THC/Alzheimers report: THC Blocks Alzheimer's Plaque Formation. Seems legitimate to me.

The blocking of the plaque formation isn't the ideal treatment. Plaque is probably normally broken down by brain cells. But the decay of the ability of cells to break down plaque is probably what causes Alzheimer's. I did a post on that too: Aged Brain Waste Removal Mechanism Leads To Alzheimers.

Also, apples help: Apple Juice Improves Brains Of Alzheimer's Mice.


It is not clear to me exactly what the mechanism is for this benefit. It might speed beta amyloid breakdown. Or it might speed breakdown of some other harmful substance that accumulates more due to the presence of high levels of beta amyloid.

The compound these scientists used to achieve this effect might not work well in human bodies. But they've at least identified a very good target for drug development.

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