In vivo analysis of APP functional domains

Coordinator:    Prof. Dr. Ulrike Müller
Institution: Institut für Pharmazie und Molekulare Biotechnologie
The role of APP as the precursor protein of the β-amyloid peptide, that is deposited in extracellular plaques in Alzheimer´s Disease (AD) is well established. In contrast, its physiological function is still largely unknown. APP is a highly complex molecule, that may exert important functions in its unprocessed full length form, as well as functions mediated by its fragments: therefore, alterations in the level or activity of certain APP-fragments (e.g. lowering of APPsα, altered levels of AICD), in addition to Aβ accumulation might play a critical role in the pathogenesis of AD.

Two major obstacles complicate the analysis of APP functions in vivo.
Firstly, as APP is a member of a gene family that includes in mammals the related APP-like proteins APLP1 and ALPL2, functional redundancy may compensate for the loss of essential gene functions, e.g. in knockout (KO) models (Anliker and Müller, 2006).

Secondly, another level of functional diversity may result from the complex proteolytic processing of APP (and its APLP homologues) by several secretases leading to diverse extra- and intracellular APP/APLP fragments. As these secretases have become major targets of therapeutic intervention it is of primary importance to elucidate the physiological function(s) of APP/APLPs and their processing products, because alterations in the activity or concentration of these fragments might have physiological consequences in itself.
The loss of cognitive ability on Alzheimer´s disease is fundamentally due to impaired synaptic transmission and death of neurons. This proposal is focused on investigating the biological function(s) of different domains of APP, especially their role for normal brain physiology and behavior. 
To this end, we will use (and generate) novel trangenic mouse models expressing domain-specific APP-variants (e. g. Ring et al., 2007). We expect crucial insight into the biological role of APP that are also of immediate clinical relevance for therapeutic intervention.

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Ruprecht-Karls-Universität Heidelberg   
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