Paul Seidler

The International Dementia Conference Series,  hosted by the McGill Centre for Studies in Aging resumed its biweekly events beginning September 15, 2021, with the Prion Hypothesis and Protein Aggregate Series.
Please join us on October 27, 2021 for a presentation by Paul Seidler, PhD, entitled “Reversing the amyloid fold of tau using small molecule disaggregants discovered from cryoEM structures of Tau from Alzheimer’s brain.”

Zoom Meeting Link

Meeting ID: 822 0166 6099
Passcode: 401210

Reversing the amyloid fold of tau using small molecule disaggregants discovered from cryoEM structures of Tau from Alzheimer’s brain

Aggregates of Tau are linked to Alzheimer’s Disease (AD) and dozens of related dementias.  By disrupting the prion-like seeding character of fibrillar aggregates of Tau, small molecule disaggregants offer an economical and scalable approach to treating AD and related dementias.  We determined the single-particle cryoEM structure of Alzheimer’s brain-purified Tau fibrils bound to EGCG, a canonical small molecule disaggregant.  The structure reveals a druggable binding cavity on the surface of AD Tau fibrils that is suitable for in silico drug discovery and suggests that EGCGdisaggregates fibrils by inducing charge repulsions between layered sheets of stacked protofilaments and by displacing the paired helical filament interface of AD-Tau.  We applied knowledge of the tau pharmacophore defined by EGCG to carry out in silico docking studies, which reveals additional small molecule disaggregants with physicochemical properties that support brain-permeability.  These studies illustrate that coupling atomic structure determination and classic neuropathology can be used to guide rational drug discovery.