By David N. Leff

Editor's note: Within the past week, a trio of new research results, in as many journals, have broadened understanding of Alzheimer's disease. Accounts of these findings follow.

A previously unknown molecule, just revealed inside the brain cells of Alzheimer's-disease (AD) patients, is spurring its discoverers to seek a simple diagnostic blood test, and therapies for treating the currently incurable malady.

Molecular and cell biologist Shi Du Yan is lead author of the lead article in today's Nature, dated Oct. 16, 1997. Its title: "An intracellular protein that binds amyloid-ß peptide and mediates neurotoxicity in Alzheimer's disease." Yan heads an Alzheimer-focused research laboratory at Columbia University's College of Physicians & Surgeons, in New York.

Amyloid-ß, a neurotoxic peptide, is the main ingredient of senile neuritic plaques, which cluster on the outer surface of sick and dying neurons in the brains of patients with AD. In fact, these plaques are the clinching hallmarks that confirm a diagnosis of the disease— postmortem.

Yan and her co-authors have named their unexpected molecule ERAB — endoplasmic-reticulum-associated binding protein. What it binds is amyloid-ß.

That's news in itself, because the endoplasmic reticulum, as its name implies, forms part of the cell's interior, not its outer surface, where AD plaques are known to congregate.

"I think this ERAB molecule is very important," Yan told BioWorld Today, "because it is intracellular. That makes it a marker for the early neuronal damage in AD, even before the big accumulation of amyloid-ß plaques in the extracellular space." She added, "So this is really an early event of the disease."

Yan hypothesizes that "this intracellular accumulation induces cell damage or death, which breaks the neuron's membrane and releases the amyloid-ß to the extracellular space."

ERAB turns up "widely distributed in many organs of the body," she pointed out, "so we think it is related to neurodegenerative disease and dementia, among other things. Its overexpression makes ERAB an early marker for neuronal stress, so we can stop neuronal cell death by early intervention."

Yan and her team are now engaged in trying to see if ERAB is increased in the blood or cerebrospinal fluid of AD patients. "If so," she observed, "we can use it as a diagnostic marker in living patients. But so far, we don't have any technique for detecting this marker. The other thing we are now trying to find out," she went on, "is to identify some inhibitor of ERAB, to block it from binding to amyloid-ß. That would give us some drugs for treating AD."

As a first project toward these goals, Yan and her colleagues "are overexpressing ERAB in transgenic mice, to study the polypeptide's physiological and pathophysiological functions."

An editorial in Nature describes Yan's paper as providing "the first molecular evidence that could link intracellular and extracellular amyloid-ß to neurodegeneration."

Double-Transgenic Mice Link Transforming
Growth Factor To Amyloid Neurotoxicity In Brain

Another molecular suspect in the line-up of amyloid plaque promoters surfaced last week in Nature, dated Oct. 9, 1997. This indictment's title reads: "Amyloidogenic role of cytokine TGF-ß 1 in transgenic mice and in Alzheimer's disease." Its senior author is molecular neurobiologist Lennart Mucke, at the Gladstone Institute and the University of California, San Francisco.

He and his co-authors reported that dense deposits of amyloid plaques around blood vessels in the AD brain also contain large amounts of transforming growth factor (TGF). (This cytokine normally lends a hand in immune responses, brain injury and wound healing.)

They enlisted two cohorts of transgenic mice to find and verify the TGF connection. First they engineered a colony of rodents that overproduce TGF in their brains. As these animals aged, they developed brain amyloid deposits very similar to those in humans with AD.

Then they enlisted scientists at Athena Neurosciences Inc., of South San Francisco, to collaborate in raising up a strain of mice that produce human amyloid proteins in their brains. By cross-breeding these two rodent races, they determined that TGF speeds up formation of human amyloid deposits in their brains.

"Our study," Mucke said, "has added TGF and the mediators of its actions to the list of potential therapeutic targets in Alzheimer's disease. There is now more hope than ever that better treatments for AD will be forthcoming in the near future."

Massive Genetic Screening Finds Fifth Gene Locus, Adds 10-15 Percent To AD Susceptibility Factors

Alzheimer's disease comes in two persuasions — familial and sporadic. So far, diggers into the genetic component have come up with four gene loci that predispose to AD: the amyloid precursor protein gene on human chromosome 21, presenilins 1 and 2, on chromosomes 14 and 1, respectively, and the apolipoprotein E gene (APOE), on chromosome 19.

The first three trigger early-onset AD, before the age of 60. APOE brings on the more common, late-onset disease, both familial and sporadic, as well as early-onset.

But these four AD hot spots on the human genome don't account, by a long shot, for all the genetic risk of the disease.

This week's Journal of the American Medical Association, dated Oct. 15, 1997, reports evidence of a new locus on chromosome 12. Duke University medical geneticist Margaret Pericak-Vance is lead author of the paper, titled: "Complete genomic screen in late-onset familial Alzheimer's disease."

In a two-stage genetic-linkage analysis, the co-authors screened 351 members of 54 AD-prone families, of which 141 had the disease. They found the strongest results on chromosome 12. This new genomic region apparently accounts for another 10 to 15 percent of late-onset AD.

It adds on to the 50-percent likelihood inherent in the APOE gene, which Pericak-Vance and her team identified in 1963 as the fourth AD risk factor. *

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