Tau pathology in neurodegenerative disease: disease mechanisms and therapeutic avenues

Abstract

Tauopathies are disorders associated with tau protein dysfunction and insoluble tau accumulation in the brain at autopsy. Multiple lines of evidence from human disease, as well as nonclinical translational models, suggest that tau has a central pathologic role in these disorders, historically thought to be primarily related to tau gain of toxic function. However, a number of tau-targeting therapies with various mechanisms of action have shown little promise in clinical trials in different tauopathies. We review what is known about tau biology, genetics, and therapeutic mechanisms that have been tested in clinical trials to date. We discuss possible reasons for failures of these therapies, such as use of imperfect nonclinical models that do not predict human effects for drug development; heterogeneity of human tau pathologies which may lead to variable responses to therapy; and ineffective therapeutic mechanisms, such as targeting of the wrong tau species or protein epitope. Innovative approaches to human clinical trials can help address some of the difficulties that have plagued our field's development of tau-targeting therapies thus far. Despite limited clinical success to date, as we continue to refine our understanding of tau's pathogenic mechanism(s) in different neurodegenerative diseases, we remain optimistic that tau-targeting therapies will eventually play a central role in the treatment of tauopathies.

Figure 1. The hypothesized role of tau in degeneration in various tauopathies (primary, secondary, and contributing).

In particular, gain of function may lead to misfolding and spread in secondary tauopathies. A similar process may contribute in other disorders (synucleinopathies, epilepsy) that are not classically considered tauopathies.

Figure 2. Review of mechanisms for various anti-tau therapeutics.

1. Genetically targeted therapies, such as antisense oligonucleotides (ASOs) and certain small molecules, can target tau production. 2. Small-molecule enzyme inhibitors can target posttranslational modifications (PTMs) such as acetylation (A), phosphorylation (P), and ubiquitination (Ub). 3. Methylene blue derivatives and other aggregation inhibitors were conceived of as targeting tau aggregation. 4. Tau clearance may be enhanced by molecules such as PROTACs (see above). 5. Immunotherapies (vaccines, anti-tau monoclonal antibodies) target extracellular tau. 6. Neuroprotective agents, including antiinflammatory agents, could limit the downstream impacts of tau pathology. Figure adapted with permission from Neuroscience Letters (95) and from Martin Kampmann (UCSF) with permission.