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Science Zeroes In on New Alzheimer's Drug Target

WEDNESDAY May 6, 2009 -- Drugs that control the "wrapping" of certain DNA have brought back learning and memory to mice stricken with an Alzheimer's-like disease -- and scientists now believe they know how.

The finding, published in the May 7 issue of Nature, suggests a novel therapeutic target for Alzheimer's and other diseases that impair learning and memory.

Study lead author Li-Huei Tsai, Picower Professor of Neuroscience at the Massachusetts Institute of Technology, explained that the key player here is an enzyme called histone deacetylase-2 (HDAC2). HDAC2's job in the cell is to control how tightly chromosomal DNA wraps around protein spools called histones.

Just how tightly or loose that binding is appears to influence cognition in mice, the researchers said.

Overexpress the protein and the mice have trouble learning -- for instance, to work their way through a water maze. But if HDAC2 is eliminated altogether, or if its activity is blunted with chemical inhibitors, the mouse's ability to learn improves, the team found.

The new findings help explain the results of an earlier study, also by Tsai's group. It showed that a nonspecific HDAC inhibitor-type drug could improve cognitive function in a mouse model of Alzheimer's disease.

"To the degree that more [synaptic plasticity] is better, then something that opposes HDAC2 function would be expected to improve memory or cognition -- or at least improve the ability of an animal to navigate a water maze," said Dr. Lon Schneider, professor of psychiatry, neurology, and gerontology at the University of Southern California. He was not involved in the new study.

HDACs perform a critical role in mammalian cells, including humans. The genomic material that is found within every cell does not exist as free-floating, naked molecules. Instead, it is carefully compacted into a structure called chromatin, in which DNA is wrapped around histone spools. This makes it easier for the cell to manipulate the DNA -- for instance, to move it during cell division. But there's a catch: The more tightly wound the DNA is, the less accessible it is to the proteins that read out its instructions.

By regulating the strength of DNA-histone interactions, the cell can control which genes are and are not expressed -- a level of genetic control known as epigenetics. HDACs, in general, tend to tighten histone-DNA interactions, and thereby repress gene expression.

Recognizing this, drug manufacturers have developed a number of experimental HDAC inhibitor compounds, especially for cancer, which target these enzymes.

Using a mouse model of the neurodegeneration that accompanies Alzheimer's disease, Tsai's group in 2007 found that a nonspecific HDAC inhibitor could restore learning ability and memory in the stricken mice. But there are many HDACs -- at least 11. So the question was, which HDAC was responsible for the effect?

The investigators eventually whittled the list of likely candidates to two: HDAC1 and HDAC2. After further tests, HDAC1 appeared to have no role in cognition. But HDAC2 did, and the overexpressing and underexpressing strains exhibited opposing characteristics, Tsai said.

Whereas mice that overexpressed HDAC2 were much poorer at learning than unaffected littermates, mice engineered to lack HDAC2 learned better.

At the cellular level, overexpressors had fewer synapses and dendritic spines -- that is, fewer connections from one neuron to another -- and less synaptic plasticity overall. On the other hand, mice without HDAC2 had many more of these learning-enhancing brain cell connections.

The overarching conclusion, Tsai said, "is that HDAC2 plays a very important, negative role in learning and memory. But," she added, "by no means does it say that HDAC2 is the whole picture."

Calling the study "a nice piece of work" with obvious pharmacologic implications, Schneider nevertheless cautioned that any possible HDAC2 therapeutic is years away.

For one thing, though some HDAC inhibitors are on the market as anti-cancer therapeutics, no specific drug targeting HDAC2 yet exists, and it will take years of development to reach the clinic should one be identified.

But also, Schneider said, the literature is chock-full of once-promising proteins that failed to function in humans as they did in animals.

"There are so many anti-amyloid beta drugs that have been advanced out of animals which, when given to people with Alzheimer's disease, don't do anything except cause side effects," he said. "So, on the one hand this is both a finding that one should take forward to find things that antagonize HDAC2, and it could turn out to be an effective therapeutic. But who knows?"

More information

For more information on Alzheimer's disease, visit the Alzheimer's Association.

Posted: May 2009

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