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Alzheimer Research Prize for Ulrike Müller

Ulrike Müller, professor for functional genomics at the Institute of Pharmacy and Molecular Biotechnology (IPMB) at Heidelberg University received the Alzheimer Research Prize 2008 from the Hans and Else Breuer Foundation, a privately-run organisation, for her achievements in molecular Alzheimer’s research.

With a purse of €100,000, the Hans and Else Breuer Froundation Alzheimer Research Prize is the most important Alzheimer's research award in Germany. It was presented to Ulrike Müller on 28th November at the international Eibsee Conference on “Cellular Mechanisms of Alzheimer’s Disease”, which was jointly organised by the Breuer Foundation and the German Research Foundation (DFG). This year’s prize honours Ulrike Müller’s basic work on the physiological function of the beta amyloid precursor protein APP, a key protein in the pathogenesis of Alzheimer’s.

APP protein fragments involved in the development of Alzheimer’s disease

Prof. Dr. Ulrike Müller, IPMB (Photo: University of Heidelberg)
Alzheimer’s disease is the most frequent cause of dementia in old age: approximately 30 per cent of people over 80 suffer from the disease, a total of 24 million people worldwide. The disease affects in particular brain regions that are essential for an individual’s ability to memorize and learn processes. Alzheimer’s brains are characterized by the presence of fibrillar depositions in the nerve cells as well as extracellular depositions known as plaques, which inhibit communication between the nerve cells and eventually lead to the death of the nerve cells. The plaques mainly consist of a short protein fragment, the beta amyloid peptide, which is generated through enzymatic cleavage from the much larger APP protein. APP is found on the surface of nerve cells. Since APP and its cleavage are central to Alzheimer’s pathogenesis, great efforts have been made in the last few years to investigate the mechanisms of APP cleavage and the enzymes involved. However, the natural, physiological function of APP for the nerve cell and brain function are still largely unknown.

APP proteins are essential for the development of the brain

In order to gain further insights into the natural function of APP, Ulrike Müller and her team produced genetically modified mice (known as knockout mice) that were unable to produce APP. The investigation of APP function is made difficult by the fact that APP is a member of a family of proteins that are able to take on several APP functions. Following the inactivation of an individual protein in this family, the loss of function was at least partially compensated for by the remaining, intact APP “relatives”. The importance of the APP protein family for the survival of organisms was shown through the production of combined mouse mutants. Mice who lacked two or all three APP family members died shortly after birth and revealed defects in the layer structure of the cerebral cortex.

New findings lead to new therapeutic options

Originally, it was assumed that it was specifically the overproduction of beta amyloid peptide that leads to the functional deficits that develop as Alzheimer’s progresses. However, investigations carried out in recent years have shown that the quantity of another APP cleavage product decreases as the disease progresses. This peptide, APPsalpha, is cleaved from APP by alpha secretases within the beta amyloid region. Thus, the process not only leads to APPsalpha, but at the same time prevents the production of harmful beta amyloid. Using new genetically modified mouse models, Ulrike Müller’s team has now been able to show that the APPsalpha fragment also has an essential function for the nervous system and in particular for spatial learning, memory and the efficiency of nerve cell communication.

These basic findings are of great interest for the development of therapeutics. The objective is to develop medications that stimulate the generation of APPsalpha at the same time as counteracting the generation of beta amyloid and its deposition in plaques.

 Literature:

Ring, S. et al. (2007) J. Neuroscience, 27, 7817-7826.

Herms, J. et al. (2004) The EMBO J. 23, 4106 - 4115.Source: University of Heidelberg, Press Office - December 2007

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