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Reducing Alzheimer's Protein Eases Deficits In Mice


SAN FRANCISCO -- Reducing levels of one of the proteins involved in Alzheimer's disease appears to prevent some of memory loss and learning difficulties -- at least in experimental mice.

SAN FRANCISCO, May 4 -- Reducing levels of one of the proteins involved in Alzheimer's disease appears to prevent some of memory loss and learning difficulties -- at least in experimental mice.

Researchers here crossed mice prone to develop an animal form of Alzheimer's with other mice lacking the gene for the protein tau, according to Lennart Mucke, M.D., of the University of California's Gladstone Institute of Neurological Disease.

Some of the offspring -- those with normal levels of tau -- went on to develop neurological deficits, but those with reduced tau were protected, Dr. Mucke and colleagues reported in the May 4 issue of Science.

The main target for Alzheimer's therapy has been amyloid-beta, the researchers noted, because it appears to be the major actor. Indeed, several therapeutics aimed at amyloid-beta are in clinical trials.

But Dr. Mucke cautioned that a single approach is probably not going to beat Alzheimer's. "I think tau is a worthy target," he said.

Although the experiments are preliminary, Dr. Mucke said in an interview that drugs are known that -- in culture, at least -- mimic the reduction in tau that he and colleagues created genetically.

"I think there is a real possibility to do this pharmacologically," he said.

But he cautioned that much more research is needed before the approach can be tested in humans. For one thing, he said, his animals were lacking in tau from birth and so were adjusted to low levels.

It's not clear what would happen if tau were blocked later in life, once the experimental animals had developed neurological deficits. "Could we reverse the memory loss?" he asked. "Would there be toxicity?"

He and colleagues are conducting those experiments, which mimic how Alzheimer's therapy might be expected to take place in humans.

In the current experiments, the researchers began with so-called hAPP mice, which express the human amyloid precursor protein and develop memory loss and other neurological defects that mimic human Alzheimer's.

Their brains -- like those of human Alzheimer's patients -- develop plaques of amyloid-beta peptide and tangles of tau.

The mice were crossed with others lacking the tau gene, to create three new strains of hAPP animals -- those with normal tau, those with one copy of the gene, and those with no copies, Dr. Mucke and colleagues reported.

Using standard Morris water maze testing apparatus, the researchers tested the various strains, using mice without hAPP but also with varying levels of tau as controls.

In the test, the animals swim through the maze to find a platform on which they can climb out.

All the control mice learned the task rapidly, as did hAPP mice with one or no copies of the tau gene. But hAPP mice with normal tau took significantly longer (at P<0.001).

The researcher also tested the animals in a similar water maze in which the platform was hidden.

Again, compared with the control mice, those with hAPP and normal tau took significantly longer to find the platform and had difficulty remembering where it was, at P<0.001. The hAPP mice lacking one copy of the tau gene were less impaired (at P<0.02), while those with no tau gene did not differ from controls.

The hAPP mice with normal tau also tended to die prematurely for unexplained reasons, as do some humans with Alzheimer's, but the animals lacking some or all of their tau lived normal lifespans, the researchers found. The difference in lifespans was significant at P<0.005.

"Amazingly, even partial reduction of tau prevented memory problems and premature deaths in our Alzheimer mice, even though their brains were full of amyloid beta," said co-author Erik Roberson, M.D., Ph.D., also of the Gladstone Institute.

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