Alzheimer's disease is the most common form of dementia and the seventh leading cause of death. An estimated 35.6 million people worldwide is living with dementia and the number is expected to double approximately every 20 years. This is directly attributable to the increasing aging of the world's population. Alzheimer's disease accounts for an estimated 60 to 80% of dementia cases (www. reuters.com). As a consequence the scientific community is urged to design strategies to halt AD progression.Cell Permeable Peptides are particularly appealing tools in chronic brain degenerative disorders, since they are stable, they can be delivered systemically, but most importantly they penetrate the Blood Brain Barrier. Amongst them, D-JNKI1, a peptide that specifically blocks JNK action, was used successfully in an in vivo model of AD. We showed that D-JNKI1 is able to revert memory dysfunction and synaptic dysfunction, which is a major early neurobiological phenomenon in AD. Chronic administration of D-JNKI1 did not lead to any major side-effects. With this project we would like to characterise better the contribution of JNK signalling in synaptic dysfunction. Most importantly, we have designed a new generation of JNK inhibitors that target specifically JNK3, the brain specific isoform. Such an approach will allow us to overcome a major disadvantage of CPPs since these potential therapeutical tools cannot target specific cells/organs and can thus lead to side effects when administered for prolonged periods. The designed inhibitors will be tested for their efficiency in well-established models in our lab.By the end of this project we will have gained important information on the impact of JNK in synaptopathy and we will elucidate the potential use of JNK inhibitors as new therapeutic targets in AD.