REDUCTION OF β-AMYLOID AND PHOSPHO-TAU IN TRANSGENIC MICE BY A NOVEL FUSION PROTEIN BIVALENT FOR A GENERAL AMYLOID INTERACTION MOTIF (GAIM)

Abstract

for the development of both symptom modifying and disease modifying therapeutics. Tau oligomers are toxic to neurons, inhibit long term potentiation in hippocampal slices, impair the formation of associative fear memory in mice, and induce the propagation of tau pathology during disease progression. Tau oligomer specific antibody has been used in a mousemodel of tauopathy to reduce the propagation of tau pathology and improve motor impairment and cognitive deficits validating tau oligomers as a target for drug development. Methods: A highly diverse library of 100,000 druglike small molecules was screened using AlphaLISA for detection of tau self-association, hits were validated and dose response and neurocytotoxicity assays were performed. Medicinal chemistry analysis was used to select hits for secondary assays. Stably transfected cell lines were established for tau oligomer formation assays. Acute toxicity of selected tool compounds was assessed in wild type mice. Proof-of-concept studies in the JNPL3 mouse model (Taconic) were initiated to demonstrate target engagement in vivo and to validate the screening approach. Results: About 60 druglike molecules predicted to have good CNS penetration were selected from 11 chemical series and 19 singletons. The most active hits of 8 series were chosen as tool compounds and for lead development. Some of these compounds showed good dose response in the cell assay. The acute toxicity evaluation showed no effect on the wild type mice at high, medium and low doses. Studies of tau oligomer and larger aggregate formation in the JNPL3 mice are ongoing. Conclusions: Small molecule inhibitors of tau oligomer formation have been advanced to animal studies. This presentation focuses on the progress of the in vivo studies.