Generation of tau dephosphorylation-targeting chimeras for the treatment of Alzheimer's disease and related tauopathies.
Sci Bull (Beijing)
; 69(8): 1137-1152, 2024 Apr 30.
Article
en En
| MEDLINE
| ID: mdl-38341350
ABSTRACT
Abnormal hyperphosphorylation and accumulation of tau protein play a pivotal role in neurodegeneration in Alzheimer's disease (AD) and many other tauopathies. Selective elimination of hyperphosphorylated tau is promising for the therapy of these diseases. We have conceptualized a strategy, named dephosphorylation-targeting chimeras (DEPTACs), for specifically hijacking phosphatases to tau to debilitate its hyperphosphorylation. Here, we conducted the step-by-step optimization of each constituent motif to generate DEPTACs with reasonable effectiveness in facilitating the dephosphorylation and subsequent clearance of pathological tau. Specifically, for one of the selected chimeras, D16, we demonstrated its significant efficiency in rescuing the neurodegeneration caused by neurotoxic K18-tau seeds in vitro. Moreover, intravenous administration of D16 also alleviated tau pathologies in the brain and improved memory deficits in AD mice. These results suggested DEPTACs as targeted modulators of tau phosphorylation, which hold therapeutic potential for AD and other tauopathies.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Tauopatías
/
Enfermedad de Alzheimer
Límite:
Animals
Idioma:
En
Revista:
Sci Bull (Beijing)
Año:
2024
Tipo del documento:
Article
País de afiliación:
China