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Alzheimer\'s: Protein Decomposition Impaired in the Cell?

Newly discovered mechanism could be long-sought \'missing link\' in cause of disease

The suspect most often cited when discussing possible factors triggering Alzheimer\'s is the cell-toxic protein abeta, which regularly crops up in large quantities in the cerebral cortex of patients affected by Alzheimer\'s. Until recently, however, it was unclear whether it can actually enter the cell plasma and cause damage there. Bonn researchers have now succeeded in shaking the alibi of this little protein. Their findings could prove to be the long-sought missing link in the chain of factors leading up to this disease of the brain. The findings are to be published in the February edition of the specialist journal Traffic (Traffic 5, 89-101, 2004); however, the text is already available online (

In the cerebral cortex of patients suffering from Alzheimer\'s there are regularly large amounts of the protein molecule abeta. Researchers have therefore long suspected that the protein plays a key role in the genesis of the disease. Abeta can kill cells if it is artificially introduced into the cell plasma; however, normally it does not occur there. The Bonn cell biologists Dr. Anton Schmitz and Professor Volker Herzog have now discovered that abeta can in fact enter the cell plasma from its point of origin, but that as a rule it is directly decomposed again there. Their hypothesis is that, if this decomposition does not function properly, abeta can accumulate and then destroy the cells.

Abeta is a cleavage product of acute-phase protein, a major precursor protein which has been found in almost all cell types of the organism, not only in the nerve cells of the cerebral cortex. APP is formed in the numerous membrane tubes entwined around the cell core - what is known as the ER. There it is sealed in little membrane bubbles and thus transported to the surface of the cell. Sometimes, however, a kind of molecular scissors known as proteases cut up the APP in the ER such that abeta is released. Despite this it was not possible, until recently, to show that there were appreciable concentrations of abeta in the ER.

A molecular shredder

The Bonn researchers have found the reason for this: the unwanted protein fragments leave the membrane tubes immediately via certain transport channels, with some of them passing from there into a molecular \'shredder\', the proteasome, which breaks them up even further. \'However, the decomposition which takes place via a second route is just as important,\' Dr. Schmitz explains, \'namely via the
insulin-degrading enzyme IDE in the cell plasma.\' In experiments with living cells the biologists were able to show for the first time that the IDE plays a crucial part in destroying abeta in the cell plasma. Their hypothesis is that if the two methods of decomposition are impaired, in time large amounts of abeta molecules can accumulate in the cell plasma and eventually destroy the cell.

\'In many patients where Alzheimer symptoms become apparent at an early age - i.e. at ages 50-55, researchers have in the meantime been able to show that there is over-production of abeta,\' Dr. Schmitz adds. \'In most cases, however, the disease does not begin until much later. And it is this group of older patients which in some cases also show reduced IDE activity.\' What is more, in older people the protein shredder frequently no longer functions as well as it used to; perhaps in these patients, therefore, an impairment of the decomposition of abeta triggers Alzheimer\'s.

The findings of the Bonn researchers close a gap which had long remained a mystery to researchers into Alzheimer\'s disease: it was known that cells into which abeta is artificially introduced are destroyed, likewise that the IDE activity is reduced in some patients. \'However, nobody previously knew if and how abeta can enter the cell plasma at all,\' Dr. Schmitz says. \'And what is also new is that it is decomposed there by proteasomes and IDE.\'

Contact persons:
Professor Volker Herzog
Institute of Cell Biology of the University of Bonn
Tel.: ++49-228-735301
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Dr. Anton Schmitz
Tel.: ++49-228-735313
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