Targeting the ensemble of heterogeneous tau oligomers in cells: A novel small molecule screening platform for tauopathies

Publication date: Available online 22 October 2019Source: Alzheimer's & DementiaAuthor(s): Chih Hung Lo, Colin Kin-Wye Lim, Zhipeng Ding, Sanjula P. Wickramasinghe, Anthony R. Braun, Karen H. Ashe, Elizabeth Rhoades, David D. Thomas, Jonathan N. SachsAbstractObjectiveUnderstanding the heterogeneous pathology in Alzheimer's disease and related tauopathies is one of the most urgent and fundamental challenges facing the discovery of novel disease-modifying therapies. Through monitoring ensembles of toxic and nontoxic tau oligomers spontaneously formed in cells, our biosensor technology can identify tool compounds that modulate tau oligomer structure and toxicity, providing much needed insight into the nature and properties of toxic tau oligomers.BackgroundTauopathies are a group of neurodegenerative disorders characterized by pathologic aggregation of the microtubule binding protein tau. Recent studies suggest that tau oligomers are the primary toxic species in tauopathies.New/Updated HypothesisWe hypothesize that tau biosensors capable of monitoring tau oligomer conformation are able to identify tool compounds that modulate the structure and conformation of these tau assemblies, providing key insight into the unique structural fingerprints of toxic tau oligomers. These fingerprints will provide gravely needed biomarker profiles to improve staging of early tauopathy pathology and generate lead compounds for potential new therapeutics. Our time-resolved fluorescence resonance ene...

Source: Alzheimer's and Dementia: The Journal of the Alzheimer's Association - October 24, 2019 Category: Geriatrics Source Type: research