Mechanisms That Prevent Alzheimer's Disease: Enzymatic Activity Plays Key Role

Main Category: Alzheimer's / Dementia
Article Date: 17 Feb 2009 - 1:00 PDT

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In a project involving the collaboration of several institutes, research scientists of the Johannes Gutenberg University Mainz have succeeded in gaining further insight in the functioning of endogenous mechanisms that protect against the development of Alzheimer's disease. It was found that the activity of the enzyme α-secretase is mainly responsible for the protective effect. "In the past, we had already postulated that the enzyme α-secretase was involved in preventing the formation of the cerebral plaques characteristic of Alzheimer's disease and also enhanced cerebral functions, such as learning and memory capacity," explains Professor Falk Fahrenholz of the Institute of Biochemistry at Mainz University. His research group has been working in cooperation with the University Medicine's Clinic of Psychiatry and Psychotherapy and the Central Animal Laboratory Facility (ZVTE) to discover the causes of these beneficial effects of α-secretase. The specialist publication Journal of Alzheimer's Disease (JAD) presents the results of this project in its latest issue, to appear in February 2009.

The α-secretase is an endogenous enzyme that is present in the nerve cells of the brain, where it is responsible for the cleavage of a specific protein. The result is a soluble protein fragment that promotes the growth of nerve cells and thus prevents the development of cerebral deterioration. However, if the enzyme β-secretase is active, a chain reaction is initiated that subsequently results in the development of Alzheimer's disease and, in most cases, in the complete loss of memory capacity. "You could say that α-secretase is the good enzyme and that β-secretase is the bad enzyme," Fahrenholz comments. "We now want to find out how to activate this 'good' enzyme or increase its concentrations in the brain as a way of combating this disease."

With this in view, the collaborating partners have been investigating whether the positive effects of α-secretase are attributable to its enzymatic activity or whether the protective effect is due to other properties of the enzyme. Enzymes play an important role in the metabolism as they control, regulate, and catalyze numerous biochemical processes. "The α-secretase enzyme is a highly complex one, with many other functions. For example, it also relays signals from the intercellular space into cells and interacts with molecules on other cells." Following investigations in a transgenic mouse model, Fahrenholz and his colleagues have now established that it is the enzymatic activity alone that guarantees the protective effects. If this activity is neutralized, the laboratory mice exhibit the symptoms that are characteristic of Alzheimer's disease: impaired learning ability, poor memory capacity, and the build-up of plaques. It is thus possible that the enzymatic activity of α-secretase could represent the starting point for the development of future treatments.

At the same time, the researchers were able to confirm with their experiments that it is not the plaque build-up itself that is responsible for the loss of memory capacity. The cytotoxic substances that accumulate in plaques only destroy neuron synapses when they are still in solution. Professor Fahrenholz concludes: "It is important to consider other aspects in addition to the plaques themselves, particularly their precursors, which are a real cause of the disease."

Anja Schroeder, Falk Fahrenholz, Ulrich Schmitt
Effect of a dominant-negative form of ADAM10 in a mouse model of Alzheimer's Disease
Journal of Alzheimer's Disease, February 2009, Volume 16:02

Mainz Universitaet
http://www.uni-mainz.de

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