Tau pathology in neurodegenerative disease: disease mechanisms and therapeutic avenues.
J Clin Invest
; 133(12)2023 06 15.
Article
en En
| MEDLINE
| ID: mdl-37317972
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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Enfermedades Neurodegenerativas
/
Tauopatías
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
J Clin Invest
Año:
2023
Tipo del documento:
Article
Pais de publicación:
Estados Unidos