Recent developments with tau-based drug discovery

ABSTRACT

Introduction: Alzheimer’s disease (AD), which accounts for three fourth of all cases of dementia, is a major public health problem in modern society and, yet, there is no effective treatment available that can prevent or inhibit this chronic progressive neurodegenerative disease. A major current drug target is intraneuronal abnormally hyperphosphorylated microtubule-associated protein tau which is a histopathological hallmark of this disease and of a family of neurodegenerative diseases called tauopathies.

Areas covered: In this review, the authors discuss a growing number of studies that describe the nature and mechanism of tau pathology and various drug discovery options and most recent developments in tau-based therapeutics. PubMed was used to obtain relevant literature while clinicaltrials.gov site and Google search were employed to obtain the latest information on tau based AD clinical trials.

Expert opinion: In authors’ opinion, loss of neuronal connectivity leads to the hyperphosphorylation of tau and is thus a key therapeutic target. Rescue of neuronal connectivity loss and hyperphosphorylation of tau are most promising approaches. Consequently, tau immunotherapy has a high therapeutic potential.

KEYWORDS:

• Alzheimer’s disease
• hyperphosphorylation of tau
• microtubule-associated protein tau
• neurogenesis
• neuronal connectivity
• neurotrophic support
• synaptic plasticity
• tauopathies

Article highlights

• Abnormal hyperphosphorylation of tau is a key lesion of Alzheimer’s disease and related tauopathies the density of which correlates with the degree of dementia and is a major focus of drug discovery.

• The oligomeric stage of the hyperphosphorylated tau is mainly responsible for neurotoxicity and hence is a promising drug target.

• Current major tau-based therapeutic efforts include tau immunotherapy, inhibition of tau hyperphosphorylation, inhibition of tau aggregation, and promotion of neuronal connectivity.

• Two novel therapeutic approaches are the inhibition of both tau and Aβ pathologies by passive immunization with an antibody to the amino-projection domain of tau, tau6-18, and the prevention and inhibition of the AD pathology by chronic treatment with a neurotrophic compound, P021.

• Phase I human clinical trials on both active and passive tau immunotherapy have shown no major safety concerns and Phase II studies are in progress.

This box summarizes key points contained in the article.

Acknowledgments

We thank Gisela Ramirez for secretarial assistance.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

The authors’ work was supported in part by the New York State Office of People with Developmental Disabilities, NIH grants AG019158, AG028538, the Alzheimer’s Association, (Chicago, IL) grants IIRG-00-2002, HRG-05-13095, Zenith Award ZEN-12-241433, and the Alzheimer’s Drug Discovery Foundation, (New York), NY grant 20121203.