Alzheimer's Club

"New evidence says many devastating brain diseases may share the same cause—clumps of protein debris that clog the circuitry. It could lead to new drugs for millions of aging Americans.

Brain diseases lay waste to their victims in many different ways, most of them fatal. Alzheimer's robs patients of memory. Parkinson's ravages brain regions that coordinate movement. Huntington's unleashes uncontrollable spasms. Lou Gehrig's disease vanquishes the nerve cells that control the muscles. Researchers have long assumed the causes of these and other degenerative disorders are as disparate as their symptoms.

But that assumption is being turned upside down, a stunning development with profound implications for the 6 million Americans with these ailments—and the millions more to come as baby boomers age. Many researchers now believe most of these disorders share a common origin: clusters of deformed proteins that pile up in the brain over the years, slowly poisoning brain cells. Like globs of molecular glue, the protein debris wreaks havoc inside brain cells, clogging communication channels and gumming up nutrients and other necessary chemicals.

The new thinking provides crucial clues to devising the first treatments to attack the molecular origins of Alzheimer's and other brain diseases. Instead of having to start drug development from scratch for every disease, researchers hope they can recycle similar therapeutic strategies to treat several brain disorders.

"The convergence is incredible. Everything is falling into place. I'm hoping not to be working on these diseases in 10 or 15 years," says Harvard Medical School chemist Peter Lansbury, who studies Parkinson's and Alzheimer's. He envisions a day when people will routinely get genetic tests to spot the threat of brain decay, followed up with brain scans every few years for those at risk. At the first hint of trouble patients could preemptively take cluster-blocking drugs, just as millions take cholesterol drugs to prevent heart disease.

Little biotechs and pharmaceutical giants alike are racing to devise drugs to block the deadly clusters. They are focusing first on Alzheimer's, by far the brain's most common degenerative disorder. Praecis Pharmaceuticals, in Waltham, Mass., has crafted a compound dubbed Apan, now in early human tests, which prevents toxic bundles from forming by latching on to them like Velcro. Canada-based Neurochem has designed a drug to block sugarlike structures called glycosaminoglycans, which help protein fragments form bundles; the compound prolongs survival of mice with Alzheimer's-like symptoms and is in early human testing.

"There is a new air of hopefulness after a long time without much hope," says Zach Hall, president of EnVivo Pharmaceuticals and former head of the National Institute of Neurological Disorders and Stroke.

But devising new drugs may take a decade or more, and it will be difficult to target such a delicate organ without causing side effects. This winter Elan Corp. had to halt trials of its Alzheimer's vaccine after it was linked to brain inflammation in 15 of 360 patients.

Nor is there proof that protein clusters cause brain-cell death rather than result from it; the evidence is especially sketchy for amyotrophic lateral sclerosis, or Lou Gehrig's disease. It isn't known why the brain is so vulnerable to protein globs, which presumably form in other organs, too. Researchers figure the brain is more sensitive because most neurons are created in childhood and are never replaced, whereas in most other organs cells constantly turn over.

"We have so little knowledge that we may be being dangerously simplistic," cautions Mihael Polymeropoulos, a geneticist at Novartis.

The toxic-cluster theory arises from the sudden confluence of several independent lines of research. Some of the most powerful evidence comes from studies of patients with inherited forms of Parkinson's, Alzheimer's, Lou Gehrig's, Huntington's and related diseases. Over the past decade gene hunters have identified a dozen mutant genes that cause these diseases. Most times the mutant gene codes for a protein that boosts the formation of globs of protein debris.

The first hints about cellular debris came almost a century ago, when psychiatrist Alois Alzheimer studied the brains of demented patients after death and found them clogged with strange deposits he dubbed amyloid plaques. A few years later, similar deposits, called Lewy bodies, were found in autopsied brains of Parkinson's victims. No one knew quite what to make of these odd clumps. For decades the plaques and Lewy bodies were viewed merely as by-products of brain disease. Doctors came up with all sorts of theories, blaming Alzheimer's on factors as varied as aluminum in the water supply and a lack of key brain nutrients, and attributing Parkinson's disease to pesticide exposure or drug abuse.

In the late 1980s circumstantial evidence condemning the role of Alzheimer's amyloid plaques began to build when Harvard biologist Bruce Yankner showed, in test tubes, that the amyloid protein poisoned brain cells. Exactly why and how amyloid might harm the brain was unclear.

By the early 1990s the amyloid theory attracted the interest of chemist Peter Lansbury, who was then at MIT doing basic research on how proteins fold into their complex final structures. His chemist colleagues viewed Alzheimer's research as a dead end, but Lansbury switched his lab's focus to plaques.

Other researchers had identified several related protein fragments, called beta-amyloid, inside the amyloid plaques, but they didn't know which proteins were the bad ones. In 1993 Lansbury showed that when he put a smidgen of beta-amyloid-42 into a mixed solution of free-floating amyloid particles, it immediately caused them to coalesce into clumps. He proposed that 42 was the pathological form of amyloid and that excess amounts of it would accelerate the buildup of unnatural, toxic clusters in the brain's memory centers. Sure enough, geneticists discovered that patients with rare gene mutations that cause them to produce high levels of the 42 form usually get Alzheimer's at a young age.

At the University of California, San Francisco, neurologist Stanley Prusiner was amassing evidence that deformed proteins played a key role in another class of fatal disorders: Creutzfeldt-Jakob disease, the human version of Mad Cow; and a related malady in sheep known as scrapie.

These diseases are even more insidious than Alzheimer's because they are infectious; people contract Mad Cow disease by eating tainted beef. Scientists had long assumed these disorders must be caused by a virus, but Prusiner had proposed back in 1982 that deformed proteins called prions were the culprit. That violated the dogma that an infectious agent must contain DNA to replicate; proteins have no DNA. But Prusiner gradually proved his case, nailing down the precise molecular identity of the infectious prion in 1993, just as Lansbury was publishing his amyloid-42 work.

Prusiner proved that prions are a deformed version of an otherwise harmless protein called PrP. The bad prion form is chemically identical to the good form except that it has morphed into a highly toxic shape, like an X-Acto knife stuck in the open position. (Prusiner won the Nobel Prize in 1997 for his work.)

Lansbury noticed parallels between his Alzheimer's theory and Prusiner's prions. He showed that just as the bad amyloid-42 sped the formation of amyloid clusters, a small number of pathological prions could convert good prions to the dark side, at least in test-tube experiments. There is still debate as to whether single prions or clusters are the villains.

His idea, ahead of its time, was greeted with a yawn by biologists. "I was a wacky chemist, an outsider," he says. But Harvard neurologist Dennis Selkoe, an early champion of the amyloid theory of Alzheimer's, took notice and lured Lansbury to Harvard Medical School in 1996.

In the late 1990s the toxic-cluster theory was extended to a third major disease: Parkinson's. Geneticist Mihael Polymeropoulos, then at the National Institutes of Health, pinpointed a gene that causes a rare inherited form of the disease by spawning mutations in a protein called alpha-synuclein. When researchers then looked inside Lewy bodies, the mysterious globs in the brains of Parkinson's patients, they found abundant synuclein.

The gene findings showed Parkinson's might also result from the buildup of brain debris, in this case globs of synuclein. Lansbury's team helped build the case, proving in 1998 that the mutant synuclein proteins formed clusters more easily than normal synuclein. Meanwhile, researchers had discovered the gene for Huntington's, a fatal inherited disorder that currently afflicts 30,000 Americans. It, too, creates mutant proteins that build up into globs inside neurons.

These days Lansbury, Selkoe and other proponents of the cluster theory are suddenly in the mainstream, as the circumstantial evidence has become difficult to ignore. The biggest unanswered question is why protein globs are so deadly. The answer may lie in their unusual structure. Healthy proteins coil up into precise ball-like structures that ensure they interact only with their intended targets. Prions, beta-amyloid and synuclein, by contrast, are full of sticky structures called beta-sheets that react willy-nilly with crucial proteins.

As patients age, genetic mutations or unknown environmental factors may boost the production of deformed proteins. Or old brain cells simply may get worse at disposing of debris. Stanford University biologist Ron R. Kopito recently showed that clumps of the Huntington's protein can clog up the cell's waste disposal system. "You get these diseases because the garbage collectors go on strike," he says, "or because the in-laws move in and double the amount of garbage you produce."..."

Source: Robert Langreth. Dirty Minds. Forbes.com (15 April 2002) [FullText]