Beta-amyloid is becoming a household word, especially inhouseholds whose residents have concerns about Alzheimer'sdisease.
Neuroscientists continue to learn more and more about b-amyloid, ahallmark of the aging brain, and key component in senile neuriticplaques, by which Alzheimer's disease may be diagnosed post-mortem. Despite increasing knowledge of its biochemistry andgenetics, the actual mechanism by which b-amyloid kills off cerebralneurons, and thus degrades the senescent intellect, remains an onlypartly open black box.
At the University of Verona, Italy, pathologist Filippo Rossi is pryingup that box's lid another crack. His paper in today's Nature is titled:"Activation of microglial cells by b-amyloid protein and interferon-g."
Rossi's preliminary findings suggest that the devil is in the microglia,which infiltrate senile plaques.
Until lately, medical students learned that the glia, or neuroglial cellsfound everywhere in the brain, are there merely as structural supportsthat stick the neuronal cells together. In fact, "glia" in Old Greekmeant "glue."
Now, neuroscientists distinguish at least three kinds of neuroglialcells _ plump astrocytes, medium-size oligodendroglia and minutemicroglia.
"In our opinion," Rossi told BioWorld Today, the final toxicmolecule that destroys aging neurons is nitric oxide (NO). It isgenerated by microglia, which have been activated by b-amyloidprotein and interferon-g. The mechanism of activation," he explained,"is that this molecule [b-amyloid] activates the gene that expressesNO-synthase, the enzyme that forms nitric oxide."
Rossi, with his co-authors at Verona and the University of Milan,propose that synergism between b amyloid and gamma interferontriggers the production from microglia. of reactive nitrogenintermediates, and tumor necrosis factor, leading to neuronal cellpoisoning.
They reached these findings, in mouse and rat experiments, bymeasuring the accumulation of nitric oxide from microglial cellsstimulated by the 11-amino-acid active fragment (25-35) of the b-amyloid's full 40-to-43-moiety length. Alone, the peptide had noeffect, but did potentiate cytotoxic nitric oxide free radicals, andcaused neuronal cell loss, from microglia induced by the interferoncytokine.
Microglia Switch Hats In Senile Plaques
Such neuronal mayhem is a treasonous departure from themicroglias' normal protective mission in the brain. "These particularmicroglia," Rossi said, "correspond to macrophages elsewhere in thebody, in that normally they pick up and dispose of cellular or tissueor pathogenic debris.
"Their function in the brain is tissue repair, and defending tissueagainst microorganisms, and so on. They produce chemical signalsthat regulate the functions of other cells."
In the case of aging and Alzheimer's disease, these other cells areactivated by microglia in the presence of gamma interferon. Theyproduce two more molecules, by which, "particularly, probably withNO, the microglia kill neurons."
"We are searching for other molecules that can be produced bymicroglia, acting together with b-amyloid," Rossi said, "and havefound many. But we have to write them up in papers, and send themto the journals."
He added, "This is a model we have constructed to interpret themechanism by which in Alzheimer's disease, or in aging too, theneurons are killed, and in consequence there is intellectual failure inthe subjects."
Rossi deems this b-amyloid build-up to be part of the natural agingprocess in humans. "If you take the brains of people 85 or 90 yearsold, for example," he observed, "or 95 or 100, you find b-amyloid inthe brain. Alzheimer's disease may be considered as an acceleration,or an exaggeration, of aging in the brain."
Whether this construct could point the way to eventual therapeuticapplication, he observed, "is a very difficult question. If youunderstand the mechanism we have proposed, it could be consideredfrom a molecular point of view as an inflammatory reaction. Andtherefore this finding could be a useful step for thinking of possibletherapy _ but not therapy."
He added, "The identification of this inflammatory mechanism couldbe a relevant step for further investigation, in order to findappropriate tools that prevent the mechanism. When one hasAlzheimer's disease, there is nothing to be done. But this mechanismcan be the road to investigate the function of some molecules that wemay call, in quotation marks, `anti-inflammatory drugs.' "
Rossi noted that "many drug companies are studying anti-inflammatory drugs in order to retard, to repress, to prevent theprogress of Alzheimer's disease. Our finding could be in line withthis."
But he quickly cautioned, "This is a very, very remote possibility.What I'm saying now is between reality and fantasy."
Neurologist Bruce Yankner, of Harvard University Medical School,is a leading b-amyloid investigator, familiar with Rossi's latest work."It suggests an additional mechanism by which b amyloid may beneurotoxic," Yankner told BioWorld Today, "namely that it maystimulate the secretion of NO free radicals like microglial cells. If so,in addition to damaging neurons directly, b amyloid can also causemicroglial cells themselves to damage neurons."
Yankner noted that "the same mechanism can be used to generateoxygen free radicals too from microglial cells," and added, "It's beenshown, by our lab actually, that b amyloid can directly interact withbrain neurons, and cause them to degenerate and die. That's mediatedby the fibril form of the protein that forms abnormally in theAlzheimer's disease brain. It's not like the normally produced solubleform."
Yankner observed that "Its mechanism is unknown, but that's a directeffect on neurons, whereas Rossi reports an indirect effect throughmediation of the microglial cells.
"Prior studies have shown that these cells killed neurons," Yanknercontinued. "Rossi now sheds light on one possible mechanism bywhich that may occur, because we know that b amyloid can killneurons in the absence of microglial cells."
A Prototype Therapeutic Called Congo Red
The Harvard scientist also said that "there is a very viable therapeuticapproach to b amyloid now being avidly pursued, based onpublication by our group and others recently of small organicmolecules that prevent the aggregation of the protein in its neurotoxicform.
"The prototype of these drugs is called Congo Red," he said. "One ofthe major avenues of Alzheimer's disease drug development nowamong some of the larger pharmaceutical firms is to make analogs ofCongo Red, with the hope that they will prevent the aggregation ofthe single b amyloid molecules into the larger fibrils, which cause thetoxicity, and also cause the effect that Rossi has observed, whichcauses the mols to aggregate." n
-- David N. Leff Science Editor
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