Gliatech Inc. researchers said Wednesday they've produced thestrongest data yet to support their unique approach to developing amethod for slowing the progression of Alzheimer's disease.The Cleveland-based company has been focusing its research onreducing the build-up of beta-amyloid peptide to prevent formation ofsenile plaques in the brain. (See BioWorld Today, Nov. 11, 1993, Page2.) Dense formations of senile plaques are believed to be associatedwith dying neurons and reduced cognitive capabilities in Alzheimer'spatients.Thomas Oesterling, Gliatech's president and CEO, told BioWorld mostother companies have been working on treatment efforts aimed atpreventing production of beta-amyloid."Initially beta-amyloid was thought to be abnormal," said RobertFrederickson, Gliatech's senior vice president of research anddevelopment. "Now it's considered normal and we're saying that if youstop production of it, you could create other problems."Gliatech has been concentrating on eliminating the buildup of beta-amyloid by targeting glial cells, an approach that Frederickson said isgaining popularity.According to Gliatech, as people age, the brain naturally releases beta-amyloid, but it normally is broken down by glial cells, called microglia.That process prevents formation of senile plaques.In Alzheimer's patients, Gliatech said, beta-amyloid proteins areprotected from microglia by proteoglycans, a class of sugar-containingmolecules, which appear to be secreted by other glial cells, calledastrocytes.Based on its hypothesis, Gliatech said treatment would involvedeveloping a compound that prevents the proteoglycans from bindingto the beta-amyloid, allowing the microglia to do its work.Gliatech's researchers presented two papers Wednesday with the latestdata supporting their theories at the Fourth International Conference onAlzheimer's Disease and Related Disorders in Minneapolis.The first paper reported on tests showing that beta-amyloid is degradedby microglia and that astrocytes play a role in slowing the breakdown.One set of data focused on liquid-phase studies, in which beta-amyloidproteins were added to dishes containing primary rat microglia,astrocytes, neurons, fibroblasts or the human monocyte cell line, THP-1. The results showed that microglia and astrocytes degraded beta-amyloid whereas neurons, fibroblasts and THP-1 cells did not. Anotherset of data focused on substrate-bound beta-amyloid. In that study, theamyloid was degraded by microglia and THP-1 cells, but theastrocytes, as they grew on the proteins, secreted one or more factorsthat protected them from microglia.Another paper presented by the researchers identified several types ofproteoglycans that bind to beta-amyloid and protect it from beingbroken down. The data showed that heparan sulfate, chondroitonsulfate and dermatan sulfate proteoglycans bind to beta amyloid andthat the beta-amyloid-proteoglycan complexes are resistant toproteolysis.Oesterling said Gliatech's researchers have proposed several prototypecompounds that may act to prevent the proteoglycans from binding tothe beta-amyloid."Our next step," he said, "is identifying a lead compound anddeveloping preclinical tests." n

-- Charles Craig

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