Criminal investigators used to look for the smoking gun; now they=20hunt for the bomb fragments.

In Alzheimer's disease (AD), the key clue is senile plaque. These are=20clumps of polymeric amyloid protein molecules, twisted into tight=20fibrils. Just as taggants can identify specific explosives, these=20fibrillary plaques in the brain of a deceased dementia patient verify=20that his or her severe senility was Alzheimer's disease.

In fact, to date, the only sure way to differentiate AD from other=20dementias is the postmortem finding of amyloid-beta (Ab) peptide=20fibrillary plaques in the brain.

"When Ab peptide forms fibrils," explained neuroscientist Mark=20Mattson, "then it becomes damaging to neurons. And the regions of=20the brain in which these plaques form," he continued, "are those=20involved in learning and memory, such as the hippocampus and=20association cortex." The latter, he added, "is involved in integrating=20information from sensory inputs, so we can learn and remember it."

This is a rough insight into the etiology of memory and cognition loss=20in AD patients.

Ab peptide is the product of a gene on human chromosome 21. It=20comes in two alternative sequences, 40 or 42 amino acids long. Both=20versions are present in AD plaques. Actually, these derive from a=20much larger amyloid precursor protein (APP), which runs in the=20neighborhood of 700 amino acids.

There's one salient variant to the rule that plaques of Ab peptide=20fibrils are peculiar to AD, Mattson observed. "An extra copy of that=20APP gene on chromosome 21," he said, "causes Down's syndrome.=20And all Down's individuals eventually develop AD."

Conversely, he recounted, "Senile plaques don't occur in other forms=20of dementia, except as small deposits in normal aging." He cited "the=20classic example of an isolated population on the island of Guam,=20which suffers dementia with aspects of Parkinson's disease and=20amyotrophic lateral sclerosis (ALS). Their brains contain no=20amyloid," he said, "but are loaded with neurofibrillary tangles."

Tangles, Mattson went on, "are aggregations of disorganized=20cytoskeleton protein in degenerate nerve cells."

A professor of anatomy and neurobiology at the University of=20Kentucky, Lexington, Mattson's research focuses on "studying the=20normal function of beta amyloid precursor protein, and the=20mechanisms of amyloid beta peptide's nerve cell toxicity."

Microglial Cells Crucial Co-Conspirators

He is co-author, with neurobiologist Russell Lydel, at Athena=20Neurosciences Inc., of South San Francisco, of an editorial in today's=20Nature, commenting on two related research papers in the same=20current issue.

One bears the title: "RAGE and amyloid-b peptide neurotoxicity in=20Alzheimer's disease"; the other, "Scavenger receptor-mediated=20adhesion of microglia to b-amyloid fibrils." They are from separate=20research groups at Columbia University College of Physicians &=20Surgeons in New York.

Each article identifies a different receptor for the plaque-forming=20peptide; both suggest that blocking such binding may lead to new=20drugs for preventing or treating AD.

Neuroscientist David Stern, senior author of the first paper, "cloned=20the RAGE gene a number of years ago," Mattson observed. (RAGE=20means "receptor for advanced glycation end products.")

He went on to explain that "the RAGE is on the surface of nerve=20cells, and what they've shown in this paper (whose first author is Shi=20Du Yan) is that that receptor binds to amyloid fibrils." Yan and his=20co-authors, Mattson continued, "are proposing that this is the=20mechanism that draws or attracts microglial cells to the plaques."

Microglia man the brain's outpost of the immune system in the brain.=20They scavenge and dispose of dead cells and debris, causing=20inflammation in the process.

"When we look at brains from AD patients," Mattson observed, "we=20see many more microglial cells that are bound to the plaques. And=20when this RAGE in the microglia interacts with amyloid, Yan and his=20co-authors showed, "that activates those microglia and causes them to=20produce neurotoxic substances, including oxygen free radicals."

Mattson added, "Those findings are important, and the data are very=20strong from the microglial standpoint." He is less persuaded of the=20paper's additional indictment, that of oxidative stress (free radical=20attack) in AD cell killing.

The second paper, by Joseph El Khoury and co-authors, showed that=20a scavenger receptor (SR) can also bind Ab peptide fibrils, fix the=20microglia in place and activate them. "What they've shown with SR,"=20Mattson said, "is what Yan's paper showed in the case of RAGE."

He made the point that activation of the microglial cells can be=20considered an inflammatory immune response, and observed, "there's=20increasing evidence that anti-inflammatory agents may reduce the=20development of Alzheimer's disease; clinical trials are ongoing."

The RAGE and SR findings in today's Nature suggest to Mattson=20"that one may be able to block the inflammatory reaction of microglia=20involved in AD in a specific way, without having to suppress immune=20responses in other parts of the body."

He made the point that "If one could develop antagonists that block=20binding of RAGE and SR to the amyloid, in theory that could reduce=20the damage in the environment of the plaque."

But Mattson also pointed out that "the history of being able to=20develop therapeutic agents just because you know some receptor-ligand interaction is involved and difficult."

Russell Lydel is project leader for Athena's amyloid neurotoxicity=20inflammation program. He told BioWorld Today:

"Clearly, the biotechnology industry is focused most heavily on=20attacking the enzymes that allow the amyloid beta peptide to be=20cleaved and released. In AD, I think," he added, "the biggest interest=20is in enzyme inhibitors that cleave at the amino and C terminus of the=20Ab peptide region, thus blocking production of those peptides."=20

Lydel added, "I don't think anyone has identified what the enzymes=20are. People have compounds and they have some effects, but I think=20it's unclear for the most part what they're hitting or doing. And there=20are no in vivo trials in progress that I'm aware of."

He finds it "very interesting that receptors are starting to emerge as=20potential mediators of some of these responses, and that two different=20receptors [in these two Nature papers] appear to have similar effects=20with amyloid and microglia." n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.

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