Scientists reverse Alzheimer's disease in mouse model

Scientists reverse Alzheimer's disease in mouse model

The research found that slowly depleting the presence of a certain enzyme can reverse the formation of amyloid plaques in the brain.

Just hours before this latest Cleveland Clinic Lerner Research Institute study was published, another blow to the field came when Merck announced it was discontinuing a Phase 3 clinical trial into a drug called verubecestat, following a recommendation suggesting, "it was unlikely that positive benefit/risk could be established if the trial continued".

The investigators had expected that blocking BACE1 would slow or halt the formation of amyloid plaques, but were surprised to find that it also caused existing plaques to fade away, Yan said.

Plaque load was significantly reduced in BACE1fl/fl/UbcCreER/5xFAD mice older than P120 compared with BACE1fl/fl/5xFAD littermates. That is now in phase 3 clinical trials.

Drugs targeting this enzyme will be able to successfully treat Alzheimer's in humans, the researchers said.

A sequential increase in amyloid plaque load in BACE1fl/fl/5xFAD mice from P75, P120, P190, and P300 was visible.

However, because the enzyme controls so many processes, suppressing it runs the risk of serious unwanted side effects.

In fact, mice that lack the enzyme completely suffer from severe deficits of neurological development.

To investigate whether inhibiting BACE1 in adults might be less harmful, Yan and colleagues generated mice that gradually lose this enzyme as they grow older. These mice developed in a normal, healthy manner.

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However, researchers urge caution with the results as many Alzheimer's discoveries seem to hold true in mice, then fail in people.

It is the first observed case of preformed amyloid deposition being reversed. At 10 months of age the mouse models were found have no amyloid plaque deposits at all.

This allowed the researchers to simulate both the age-related progression of Alzheimer's disease, and an associated progressive reduction in BACE1 activity.

'We were surprised it worked so well, we saw complete reversal, ' Yan, who will start as chair of the department of neuroscience at the University of CT this spring, said. "We need studies like this to find out how the two are intertwined and hopefully find the right formula to help prevent Alzheimer's disease", said Dr. Rong Zhang of UT Southwestern.

The draft guidelines suggest that improvement in biomarkers, such as amount of beta amyloid in the brain, a protein linked to the disease, may be an acceptable goal for deeming a drug successful in patients with no symptoms.

Tests on the mice subsequently show that their cognitive processes improved as the plaques were removed from their brains. The plaques have been thought for some time to play a key role in the degenerative disease, with Alzheimer's patients showing higher levels of the plaque in their brain than people without Alzheimer's.

The study was supported by grants from the National Institutes of Health. "It makes sense it might be applicable to humans as well", Kornel said.

The new study was published February 14 in the Journal of Experimental Medicine.

A study conducted at UT Southwestern's O'Donnell Brain Institute has added to the growing body of evidence that regular exercise improves brain health and reduces the risk of Alzheimer's disease.

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