FOR 1332: Physiological Functions of the APP Gene Family in the Central Nervous System

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The APP protein plays a key role in the pathogenesis of Alzheimers disease. Little is known, however, about its role for nerve cell communication in the healthy human brain. The purpose of the Research Unit is two-fold: to find out more about the proteins physiological role for learning and memory, and to enhance the understanding of APP functions with a view to developing new therapeutic approaches to treat Alzheimers disease. Alzheimers disease is triggered by deposits of insoluble protein aggregates that form plaques in the vicinity of nerve cells within the brains of Alzheimer patients. These plaques are mainly composed of the ß-amyloid peptide. The damage it inflicts on the nerve cells finally kills them. This small protein is derived via proteolysis from a much larger precursor, the amyloid precursor protein APP. So far, the normal cell biological and physiological functions of APP and its proteolytic products are largely unknown, although APP is produced in almost all brain cells, notably in regions important for memory formation. Recently, the enzymes involved in APP processing (termed secretases) have become major therapeutic AD targets and therapeutic interference with APP processing is likely to alter physiological APP functions. Thus, there is an urgent need for a dedicated research effort aimed at understanding the functional consequences of altered levels and activity of full length APP and its various proteolytic fragments in CNS physiology. Seven teams of scientists cooperate within the transregional Research Unit. They come from the universities of Heidelberg, Frankfurt/Main, Mainz and the technical universities of Kaiserslautern and Braunschweig. Using interdisciplinary methodological approaches the physiological functions of APP family proteins will be studied within the central nervous system from the molecular level to the intact organism. Within our highly interactive research projects we will study the role of APP family proteins in synapse formation and function, plasticity, learning and memory, neuroprotection and regeneration.