The amyloid beta peptide (A-beta) plays a central role in the pathogenesis of Alzheimers disease but it remains unclear how exactly this peptide impacts on neuronal viability and cognitive functions in AD patients.More and more it is believed that synaptic dysfunction and loss caused by small soluble A-beta oligomers, but not by mature fibrils deposited in the plaques, is the first sign of neurodegeneration in AD.The A beta sequence contains two boxes that may regulate the aggregation process of the peptide and therefore the first objective of the proposed project is to modify by mutagenesis these aggregation-related A-beta boxes and clarifying the connection between aggregation and neurotoxic properties of the A-beta peptide.In addition, we will set up a series of robust and reliable assays to measure synaptotoxicity caused by the A-beta oligomers in primary hippocampal neuronal cultures and in mouse models. To that aim we will in collaboration with the institute for microelectronics (IMEC) develop the Neuro-Electronic hybrid sys tem or Artificial SynApse, the neuro-electronic device that allows measuring changes in the synapse in a high throughput mode.This neuro-electronic device will make it possible to sense electrical and biochemical changes of neurons in real time upon addition of toxic A-beta to a neuronal network of hippocampal neurons. Consequently, the neuro-electronic device will allow in the long run screening for compounds that interfere with amyloid oligomers-mediated neurotoxicity.In conclusion, it is our objective to contribute to the understanding of the pathological process causing Alzheimers Disease and to development of a cure for this devastating disease.