D. Moechars, Department of Neuroscience, Janssen Research & Development, a Division of Janssen Pharmaceutica NV, Beerse.
ObjectivesA common feature in a variety of neurodegenerative diseases is the accumulation and toxic gain of function of misfolded assemblies of specific proteins. Alzheimer´s disease (AD) and Parkinson´s disease (PD) - the two most abundant forms of neurodegeneration – are respectively characterized by fibrils of hyperphosphorylated tau in intracellular neurofibrillary tangles (NFT) and aggregates of Aβ peptides in extracellular plaques or by α-synuclein fibrils that are the constituent of intraneuronal Lewy bodies (LB). More recently, it has been shown that assemblies of both tau or α-synuclein exhibit prion-like properties and spread through the central nervous system along interconnected neuronal networks suggesting that a unifying molecular mechanism may underpin the pathogenic progression in AD and PD. This prion-like propagation of pathology provides potential novel opportunities for therapeutic intervention that are currently being addressed in our group. An overview of these ongoing activities in our group will be presented.
MethodsA broad variety of as pathophysiologic relevant as possible in vitro and in vivo models of prion-like Tau propagation are being developed that in first instance allow addressing basic scientific questions in Tau propagation. Such models in second instance allow target identification, target validation and small and large molecule identification and screening of modulators of Tau propagation at the level of Tau seed uptake, Tau seed clearance, Tau protein level, Tau aggregate build up, Tau aggregate clearance and Tau spreading.
Results & ConclusionsThis presentation will review the current state of development of therapeutic interventions based on prion-like propagation Tau of pathology and will discuss progress towards.