Advances in tau immunotherapy

Recently tau protein has emerged as a viable therapeutic target for Alzheimer’s disease (AD) and multiple other neurodegenerative disorders known as tauopathies. Neurofibrillary tangles have long been known to be hallmarks of these disorders and to spread stereotypically through the brain. Further study into the toxicity of the protein has led many to conclude that these large fibrillar aggregates are likely not the most toxic state of tau, nor the form responsible for the spread of pathology through the brain. Rather the origin of early toxicity is likely the smaller aggregate, the oligomer. One of the most encouraging routes in which scientists can target these toxic conformations is by immunotherapy. Initial studies on immunotherapeutic approaches for AD focused on active vaccination with the Aβ protein, however this strategy proved to have some concerns with both safety and efficacy. While Aβ is an early mediator of toxicity in AD, tau lies downstream and without targeting it as well, toxicity will still remain. Moreover, active vaccination of both Aβ and later of tau led to inflammation and encephalitis. Therefore, a focus on passive immunotherapy with tau-specific antibodies began. Though initial studies were based on hyperphosphorylated tau epitopes, the most promising results recently have targeted forms of tau that occur early in disease and lead to decreased levels of soluble, oligomeric tau. This chapter will outline the latest advances in the field of tau immunotherapy and the aspects of the strategy that are not yet fully understood.