Current state of tau aggregation inhibitors

Abstract

Tau is an intrinsically disordered, heat stable, and highly soluble protein found primarily in the axons of the central nervous system. It belongs to the family of structural microtubule-associated proteins, the major function of which is promoting and stabilizing microtubule assembly. However, modifications to the protein generate insoluble toxic oligomers of aggregated tau which are amyloid in nature. This modification renders them ineffective in binding to tubulin to stabilize microtubule assembly. Aggregates of tau are pathological hallmarks of many neurodegenerative disorders, collectively known as tauopathies. Some of the most well-known tauopathies are Pick’s disease (PiD), progressive supranuclear palsy (PSP), corticobasal neurodegeneration (CBD), and Alzheimer’s disease (AD). AD is the 6th leading cause of death in the USA and is the most prevalent tauopathy. There are only five FDA approved drugs that can arrest the cognitive decline and other symptoms of AD temporarily, but they do not reverse or inhibit the pathology of the disease. The disease therefore continues to progress, and cognitive functions decline faster when the drugs lose their effectiveness. There is a general consensus that therapies that reduce pathology would be beneficial for treating the disease. AD is characterized by two neuropathological hallmarks – extracellular senile plaques, which are aggregates of amyloid  peptide, and intracellular neurofibrillary tangles, which are composed of tau aggregates. Initially, much of the emphasis for drug discovery for AD was focused on inhibiting or reversing the amyloid senile plaque pathology. This focus was due to the observation that familial forms of early onset AD are associated with mutations which enhanced the formation of senile plaques. Additionally, the number of dementia cases involving senile plaques outnumbers dementia cases with pure tauopathies. Recent failures of drugs targeting amyloid accumulation for the treatment of AD and new evidence further strengthening the association of tau pathology with neurodegeneration and AD cognitive impairment have placed importance on the development of tau-based therapeutics. This report discusses the current state of therapies and drugs that are available and are being developed to find an effective cure for AD and other tauopathies.