PROTAC tau degrader for the treatment of Alzheimer’s disease and primary tauopathies

Abstract

AbstractBackgroundAlzheimer’s disease (AD) is characterized by progressive decline of memory and cognitive functions. Accumulation of hyperphosphorylated tau is a pathological hallmark of AD and also plays a pathogenic role in disease progression. Proteolysis Targeting Chimera (PROTAC) technology enables the selective removal of a target protein by cellular ubiquitin‐proteasome system. Here we describe the characterization of tau PROTAC degrader developed at APRINOIA as a novel disease modifying treatment.MethodsTau degrader was synthesized by linking a proprietary tau binder from Aprinoia tau PET tracer program with a ligand of E3 ligase. The PROTAC mediated tau degradation was first evaluated in HEK293 cells expressing P301L tau, which develops tau oligomer and aggregates upon incubation with “tau seeds” from brain lysates of rTg4510 mice. The reduction of tau aggregates was measured using a HTRF based immunoassay. A similar seeding induced tau aggregation assay was established in primary neurons to confirm the degrader activity. Efficacy was further evaluated in rTg4510 mice following treatment with IV injection.ResultsPROTAC tau degrader reduced tau oligomer/aggregates in cellular models as well as in therTg4510 mice. Preliminary data suggests degrader is more effective in degradation of soluble tau oligomers in early stage of pathological tau development.ConclusionTau PROTAC degrader generated from proprietary tau warhead can selectively decrease the oligomer/aggregated tau in both in vitro and in vivo models. Current effort is focused on optimization of ADME properties of tau degrader as a promising therapy for AD primary tauopathies.