Brain enzyme treatment relieves memory lapse in Alzheimer's mice

Aug 24, 2006

An enzyme that helps neurons rid themselves of excess or aberrant proteins is required for normal brain function, according to a new report in the August 25, 2006 issue of the journal Cell. What's more, by increasing brain levels of the enzyme in mice with Alzheimer's symptoms, the researchers found they could reverse lapses of memory characteristic of the debilitating disease.

Treatments that elevate the protein, known as ubiquitin C-terminal hydrolase L1 (Uch-L1), might therefore have potential as a new therapy for Alzheimer's disease, according to the researchers. Currently available therapies have almost exclusively targeted amyloid beta (Aß), the protein responsible for the "amyloid plaques" that riddle the brains of patients with Alzheimer's disease, they added.

"By injecting what is essentially a Uch-L1 drug to raise its levels in the brain, we were able to restore a great deal of brain activity in a transgenic mouse model of Alzheimer's disease," said Michael Shelanski of Columbia University.

"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 Unpublished studies by Shelanski's group found that cells treated with Aß exhibited a rapid drop in Uch-L1, he said.

To further investigate in the current study, the researchers treated brain slices with a chemical that blocks Uch-L1 function. The treated brain tissue displayed a decline in "long-term potentiation" (LTP), a process whereby nerve connections are strengthened. LTP is regarded as the cellular basis for learning and memory.

Treatments that restored Uch-L1 levels corrected deficits in nerve transmission both in brain slices treated with Aß and in slices taken from transgenic mice with mutations that lead to elevated Aß and associated cognitive decline.

The researchers next asked whether Uch-L1 played an important role in fear conditioning, a form of learning known to be impaired in several mouse models of Alzheimer's disease.

For fear conditioning, mice treated with the Uch-L1 inhibitor and control mice were placed in a novel context (a fear-conditioning box) and exposed to a tone paired with a mild foot shock. Their ability to learn fear was tested 24 hr later by measuring "freezing" behavior in response to the box or the auditory cue. Contextual versus cued responses represent different forms of learning that depend on different parts of the brain.

A day after their exposure to the shock, mice with reduced levels of Uch-L1 showed a decrease in freezing behavior to 65% that of normal mice when placed in the box. The differences between treated and untreated mice persisted 7, 14, and 21 days after exposure to the electric shock, they reported.

On the other hand, the mice showed no differences in response to the auditory tone, suggesting variation among brain regions in the role of Uch-L1.

In mice with symptoms that mimic those found in patients with Alzheimer's disease, treatments that raised Uch-L1 greatly increased their freezing time compared to their transgenic littermates when contextual learning was assessed over time, the researchers found. Improvements in the treated animals' ability to establish a memory for fear did not depend on changes in Aß levels.

The findings provide a new window into the Alzheimer's brain that could lead to new therapies, the researchers said.

"The rapid fall in Uch-L1 activity in response to Aß raises the possibility that, in the Alzheimer's brain, Aß initiates a signaling cascade that results in the partial inhibition of proteasome activity more rapidly than is likely as the result of the accumulation of misfolded or undigestable proteins."

"Our data suggest that Uch-L1 could be an attractive target for the development of new therapeutic approaches to Alzheimer's disease, either alone or in combination with therapies that alter Aß levels."

Source: Cell Press

Explore further: Study shows effectiveness of simple, low-cost tobacco interventions in ERs

add to favorites email to friend print save as pdf

Related Stories

The largest known muntiacine found in China

12 minutes ago

Dr. HOU Sukuan from the Institute of Vertebrate Paleontology and Paleoanthropology (IVPP), Chinese Academy of Sciences reported a new species of muntiacine Euprox in the journal of Zootaxa 3911 (1) recent ...

Image: Sounding rockets launch into an aurora

37 minutes ago

The interaction of solar winds and Earth's atmosphere produces northern lights, or auroras, that dance across the night sky and mesmerize the casual observer. However, to scientists this interaction is more ...

Recommended for you

Why medical debt – and bankruptcy – are growing problems

29 minutes ago

Burdensomely high medical costs are often blamed for pushing many Americans into bankruptcy. According to the Consumer Financial Protection Bureau some 43 million Americans have unpaid medical debt on their credit reports. ...

California declares electronic cigarettes a health threat

43 minutes ago

California health officials on Wednesday declared electronic cigarettes a health threat that should be strictly regulated like tobacco products, joining other states and health advocates across the U.S. in seeking tighter ...

New cells may help treat diabetes

46 minutes ago

Starting from human skin cells, researchers at the University of Iowa have created human insulin-producing cells that respond to glucose and correct blood-sugar levels in diabetic mice. The findings may represent ...

User comments : 0

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.