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Tau has commanded much attention as a potential therapeutic target in neurodegenerative diseases. Tau pathology is a hallmark of primary tauopathies, such as progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and subtypes of frontotemporal dementia (FTD), as well as secondary tauopathies, such as Alzheimer’s disease (AD). The development of tau therapeutics must reconcile with the structural complexity of the tau proteome, as well as an incomplete understanding of the role of tau in both physiology and disease. This review offers a current perspective on tau biology, discusses key barriers to the development of effective tau-based therapeutics, and promotes the idea that pathogenic (as opposed to merely pathological) tau should be at the center of drug development efforts. An efficacious tau therapeutic will exhibit several primary features: 1) selectivity for pathogenic tau versus other tau species; 2) blood-brain barrier and cell membrane permeability, enabling access to intracellular tau in disease-relevant brain regions; and 3) minimal toxicity. Oligomeric tau is proposed as a major pathogenic form of tau and a compelling drug target in tauopathies.

Focusing on oligomeric tau as a therapeutic target in Alzheimer’s disease and other tauopathies