Fosfopeptide specifieke kinase inhibitor profilering van Withaferine A en/of Saracatinib behandeling van de ziekte van Alzheimer

Alzheimer's dementia (AD) is increasingly being recognized as one of the most important medical and social problems in older people in industrialized and non-industrialized nations. Sofar, little is known about possible changes in protein kinase activity in the pathology of AD progression. Today, kinase inhibitors upstream or downstream of amyloid-β oligomer signaling hold promise as effective disease modifying strategies to attenuate or prevent AD progression. In this respect, there is an urgent need to investigate changes in protein kinase activity and the associated signalling pathways during AD progression and the potential of these kinases to be used as diagnostic biomarkers and drug targets. The low benefit of drugs which target one single kinase has enforced research towards multitargeting kinase inhibitor strategies in AD drug-discovery and to develop brain-permeable multitargeting protein kinase inhibitors with low cellular toxicity which attenuate protein kinase hyperactivity but do not block their physiological activity levels in normal cells. In the current proposal we will combine phosphopeptidome profiling and functional kinase silencing approaches in the transgenic AD model APP23 and relevant cell and/or brain organoid models to characterize the Ser/Thr/Tyr kinome inhibitor profile of 2 promising AD modifying therapeutic compounds withaferin A and saracatinib AZD0530 which already have shown to attenuate and/or reverse AD pathology in vivo.

Trefwoorden:ZIEKTE VAN ALZHEIMER

Disciplines:Cellulaire signaaltransmissie, Systeembiologie niet elders geclassificeerd, Cognitieve neurowetenschappen, Compound screening, In vitro testen, Niet-klinische studies