Aiming at Amyloid

Researchers find possible mechanism to halt Alzheimer’s

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ORANGEBURG, N.Y.-One of the hallmarks of the onset of Alzheimer's disease (AD) is the formation of aggregates of amyloid protein in the brain. According to two new papers published in Nature Genetics, however, researchers may have identified a natural mechanism that inhibits this aggregation, offering the possibility of developing small-molecule or peptide-based therapeutics to mimic this effect in people with AD.

 Using mouse models of AD, scientists in the United States and Europe showed that the naturally occurring protease inhibitor cystatin C interacts with amyloid-beta protein in body fluids such as cerebrospinal fluid and blood, thereby preventing its aggregation and deposition in neuronal tissues. The in vivo findings support earlier studies showing the interaction of the two proteins in vitro.

 "The interaction of cystatin C with amyloid-beta acts to inhibit amyloid-beta aggregation into the oligomeric soluble forms as well as the fibrillar insoluble forms of amyloid-beta that deposit in the brains of Alzheimer's disease patients," says Dr. Efrat Levy, a researcher at the Nathan S. Kline Institute for Psyciatric Research, based here, and lead author of one of the papers.

 "From a therapeutic perspective, a biologically active small peptide or molecule containing the key functional properties of cystatin C should be developed," she adds. "We have recently received a grant from the Alzheimer's Association to develop such a cystatin C-analog that would serve to develop a novel drug for slowing, halting, or reversing disease progression. The idea is to search for a cystatin C fragment, cystatin C-derived peptides, or peptidomimetic compounds with anti-amyloid-beta properties."

 According to Dr. Mathias Jucker, lead author of the second paper and researcher at the University of Tübingen, located in Germany, the real excitement arising from the research is the over-arching biological mechanism that it defines.

 "The new concept from this and other studies is that amyloidogenic proteins can either promote each other's aggregation or inhibit it-amyloid interference," he says. But he does agree with Levy that "such an insight may be exploited for drug discovery."

 If they could develop a drug that inhibits amyloid-beta, it would represent something of a departure from the current portfolio of AD-targeted drugs that largely focus on symptom alleviation rather than disease modification (see Band-aid for the brain, on page 22).

 "The potential of this unmet needs market has attracted considerable attention from drug developers," noted Adriana Rusu, a Frost & Sullivan research analyst, in a recent report on the AD market opportunities. "The first wave of disease-modifying drugs is likely to reach the market within the next couple of years, and in combination with symptomatic drugs, could enhance treatment options in this growing market."

 According to Rusu, the combination of improving diagnostic techniques and an increasing disease prevalence due to aging baby boomers will push the U.S. AD market from its current $2.5 billion to more than $4 billion by 2013. Further impetus to companies entering the disease-modifying market will come from the onslaught of generic versions of the symptom-relieving drugs in the next few years.

 Adding potential interest to the concept of a cystatin C mimetic is the fact that the protein is involved in other biological processes that could potentially take it beyond AD and into other neurological disorders.

 "We have accumulated data showing that cystatin C can protect neuronal cells and cerebral smooth muscle cells from various insults that cause cell death, including toxicity induced by oligomeric and fibrillar amyloid-beta," Levy says. "Finding a peptide or molecule that has a neuroprotective effect-whether the same one with the anti-amyloid-beta properties or another one produced in our search-would add important benefit to these studies."

 Neither Jucker nor Levy have been contacted by anyone from the pharmaceutical industry about their work, but Levy for one is not averse to the idea. "Any contact with the industry would significantly speed up the development [of a potential drug]," she says.

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