Titre: Selectively targeting pathological tau signaling in AD and related dementia Abstract Tauopathies contribute to multiple, devastating neurodegenerative disorders, including Azheimer's disease and related dementia (ADRD), Fronto-Temporal lobe Dementia (FTD), and Chronic Traumatic Encephalopathy (CTE), for which there are no effective therapies. Although each tauopathy has a disease specific phenotype, histological presentation, morphology, and neurological presentation, all are associated with misfolded tau and altered phosphorylation leading to a gain of toxic function. The search for a common pathogenic mechanism has been hindered by this clinical diversity. However, recent findings provide new insight into tau pathology. The first is identification of conformation specific tau antibodies that recognize different pathological forms of tau, suggesting conformational diversity within the tauopathies. This was corroborated by our recent identification of a novel feature: Exposure of an N-terminal sequence that is sequestered in non-pathogenic tau. This 17 amino acid domain comprises a Phosphatase Activation Domain (PAD) and acts as biologically active motif that is necessary and sufficient to activate a signaling pathway involving protein phosphatase 1 (PP1) and glycogen synthase kinase 3 ? (GSK3?) providing therefore a molecular basis for altered kinase activities in AD and tauopathies. Interestingly, this PAD region sequestered in normal brain, is aberrantly displayed in all pathological forms of tau examined to date and is a necessary component of at least two forms of tau toxicity: inhibition of fast axonal transport and cell toxicity in culture. Therefore, PAD domain represents a novel attractive target for small molecule therapeutics to treat tauopathies and ADRD. The monoclonal antibody (TNT1), specific to the Tau-PAD epitope, blocks toxic effects of pathogenic tau. A small molecule that can inhibit the PAD/TNT protein-protein interaction can theoretically inhibit the actions of pathogenic Tau; and by binding to the PAD domain can be developed as a radiotracer to map disease progression. The phenotypic effect can be shown in rescue of axonal transport in squid axons.
Aim 1) To identify small molecules hits that inhibit PAD/TNT1 interaction by selectively binding to PAD;
Aim 2) Limited med chem hit optimization and phenotypic assay development to identify an in vitro chemical probe for future development as therapeutic or radiotracer.
New therapeutics for Alzheimer's disease (AD) and tauopathies are desperately needed but have been hindered by the diversity of tau species. Tauopathies are all associated with misfolded tau protein, but differ in the neuronal population affected as well as the isoform composition and structure of tau aggregates involved. The exposure of an N-terminal sequence PAD domain that is sequestered in non-pathogenic tau represents an early pathogenic event in AD and related dementia, and constitutes an opportunity for the development of PAD ligands as a translational biomarker and novel approach to treating and diagnosing tauopathies, which is the rationale for this proposal.
