Tau-based therapeutics for alzheimer's disease and related tauopathies

Abstract

Neurofibrillary pathology composed of the microtubule associated protein tau is a characteristic feature of Alzheimer's Disease as well as multiple rare tauopathies such as FTLD-tau and Progressive Supranuclear Palsy. In each case, the density and distribution of the tau lesions correlates with the extent of neuronal loss and with the clinical progression of the disorder. Moreover multiple mutations in the tau (MAPT) gene have been shown to cause FTD linked to chromosome 17 establishing that tau dysfunction is sufficient to cause neurodegeneration. These mutations impact tau in different ways but significantly all are predicted to enhance tau aggregation suggesting that protein misfolding is a critical component of the neurodegenerative cascade. As a result of these findings, considerable research effort has focused on determining the mechanism of neurofibrillary degeneration and on identifying potential therapies for the treatment of tauopathy. Kinase inhibitors that have been postulated to block tau hyperphosphorylation and toxicity, aggregation inhibitors designed to prevent the formation of filamentous inclusions, and various approaches to enhance the clearance of pathological tau have been proposed and have undergone varying degrees of preclinical development. More recently, therapeutic antibodies designed to block the transmission and spreading of tau pathology have also received considerable attention. However despite the significance of tau and the high level of research activity, only a handful of potential small molecule drugs have progressed into early clinical trials and to date none of these have produced robust evidence of clinical efficacy. Several issues explain this relative lack of success, in particular there remains no consensus on the pathogenic mechanism that underlies tau-based neurodegeneration and in addition there is currently a lack of validated, tractable targets for which translatable biomarkers exist to enable clinical development. Despite this there remains grounds for considerable optimism with the recognition that tau likely spreads through the brain in a prion-like manner and the development of the first tau PET imaging agents providing new opportunities for drug discovery. This presentation will therefore review the current state of tau therapeutic development and will discuss progress towards translating preclinical findings into effective treatments for patients with tauopathy.