For years, the number of Alzheimer patients increases in Germany. Experts estimate that currently about 650,000 people suffer from the most frequent form of dementia. The diagnosis of this incurable disease is still difficult. Although special tests evaluating the memory supply initial evidence and magnetic resonance imaging (MRI) visualizes the reduction of brain volume in the frontal- and cranial lobes typical for Alzheimer, those examinations are not enough to really demarcate Alzheimer clearly from other dementias.
Diagnosis – but too late
A definite diagnosis by means of a fine tissue analysis of the brain is not possible until the patient has died. The analysis enables the pathologist to finds the so-called plaques, the typical sediments in the brain. Recently, Berlin scientists found relevant details about the development of the disease. Based on those findings, Gerd Multhaup and his team of the Institut für Chemie und Biochemie der Freien Universität Berlin (institute for chemistry and biochemistry at the Free University of Berlin) will develop a test in the years to come which will enable an earlier and more reliable diagnosis.
The researchers turn a realization of the past few years into account. According to that, the protein Abeta-42 plays the leading part in a process during which Alzheimer patients are getting more and more forgetful. The protein composed of 42 amino-acids causes more and more neurones to mortify in the brain. Abeta-42 is a fragment of a much larger protein. This so-called amyloid-parent protein (APP) sits in the membranes coating the nerve cells. APP transmits signals from outside the cell to the inside. Once it concluded its mission, it dissipates piece by piece. In the neurones, a special class of enzymes called secretases are deployed for that purposes. They work like molecular scissors cutting proteins like APP at different locations.
Molecular scissors only cut fragmentary
Depending on where the cuts are set, they create different sizes of fragments. Most of these fragments are not stable and are disjointed in single amino-acids by the cells. But the complete degradation of APP is not always successful. The researchers around Multhaup have found out how this happens. According to them the amino-acids in the amyloid-parent protein are arranged in a way where two of those molecules embed together. “Like Siamese twins those two molecules at that spot are interconnected so strongly that the secretase cannot proceed any further and cut amino-acids”, explains Multhaup. Together with his colleagues he reported about this new discovery in the professional magazine EMBO-Journal.
He assumes that in Alzheimer patients an eminent number of those stabile Abeta-42 molecule double packs remain. The researchers do not know a lot about the reasons – but they for sure know about the consequences: “Presumably the double packs embed even closer in Alzheimer patients and perforate the membranes of the neurones”, says Multhaup.
After accomplished work, the Abeta-42 molecules agglomerate between the neurones building gigantic aggregates. These amyloid plaques visible under the microscope are the harmless final storage of the actual malefactor – and not the trigger of Alzheimer as assumed before.
Sequence of the amino-acids determines the degradation
The researchers used human kidney cells for their experiments and modified them genetically to produce increased APP. This enabled Multhaup and his team to succeed in changing the amino-acid sequence in the amyloid-parent protein at critical locations. Even the merest difference in this area leads to the APP molecules not clinging so tightly any more thus reducing or completely stopping the development of Abeta-42. But the researchers were able to prove another fragment developing during further degradation by secretase and four amino-acids short of Abeta-42. “Abeta-38 is much less stabile and does not do any damage in the neurones because it does not develop double packs”, explains Multhaup.
His colleague Jens Wiltfang, neurologist at the University of Nuremberg-Erlangen, was able to show that the concentration of Abeta-38 in the brain-medulla fluid (liquor) of Alzheimer patients was particularly low and the Abeta-42 concentration especially high. “That is a hundred percent in accordance with what we have observed on a molecular level”, says Multhaup. “The proportions of the fragments do not just show whether the Alzheimer disease broke out yet but also how far it advanced.”
Not fit for routine examinations yet
The Berlin researchers want to make use of their cognizance and develop a test discovering the dementia disease easily and fast. The starting position is not that simple as Multhaup acknowledges: “Although we can identify APP degradation products such as Abeta-42 and Abeta-38 in the blood today, the verification is extremely complex and really not suitable for a routine examination”, says Multhaup. The entire procedure has to be essentially simplified and tested on many test persons before the procedure is applicable for routine diagnosis.
Other Alzheimer researcher are sceptical and do not believe in a rapid realization of Multhaup’s idea: “I consider it extremely difficult since so far it was not proven whether there is really a lot of Abeta-42 and little Abeta-38 in all Alzheimer patients”, says Christian Haass, professor of biochemistry at the Adolf-Butenandt-Institute of the Ludwig-Maximilian-University in Munich. But this kind of doubts will not hold the researchers at the FU Berlin back: “To push the development of the early test, we plan to found an own company”, reports Multhaup. “No later than five years down the road the test should be available on the market.”