Project: CNS delivery of the secreted amyloid precursor protein ectodomain APPsa: Effects on brain physiology and therapeutic potential for Alzheimer’s disease

Synaptic dysfunction, cognitive decline, and deposition of the ?-amyloid peptides (A?), derived by proteolytic processing from the amyloid precursor protein (APP), are the hallmark features of Alzheimer´s disease (AD). Whereas the contribution of APP proteolysis to the formation and deposition of amyloid plaques are well-known, we still ignore the normal physiological functions of APP and of its proteolytic fragments. Increasing amount of evidence demonstrate the essential role of endogenous APPs? for synaptic plasticity and cognition and its functions in neuroprotection against stress and overexcitation. Our goal is to further characterize the effects of APPs? overexpression for normal brain physiology and to evaluate vector-mediated APPs? expression for its potential as novel therapeutic approach for AD. Recent progress made in vector-mediated gene delivery led to the development of very efficient tools allowing widespread delivery of genes of interest into brain, particularly the hippocampus. The two most promising vector systems for CNS gene delivery, AAV and lentiviral vectors will be optimized for APPs? delivery and efficient release of expressed APPs? from transduced cells. This way we will investigate effects of APPs? overexpression for brain physiology and the therapeutic potential of APPs? delivery in transgenic models of AD on synaptic density, synaptic plasticity and cognitive behavior.

Acronym	nEUAPPs
Network	ERA-NET NEURON II
Call	Novel Methods and Approaches towards the Understanding of Brain Diseases

Project partner

Number	Name	Role	Country
1	University of Heidelberg	Coordinator	Germany
2	Katholic University of Leuven	Partner	Belgium
3	University Paris Descartes	Partner	France
4	Paul-Ehrlich-Institut	Partner	Germany