Profiling tyrosine kinase inhibitors as AD therapeutics in a mouse model of AD.
Mol Brain
; 16(1): 63, 2023 08 14.
Article
en En
| MEDLINE
| ID: mdl-37580778
Alzheimer's disease (AD) is a neurodegenerative disease characterized by Aß deposition, tauopathy, neuroinflammation, and impaired cognition. The recent identification of associations between protein kinases and AD pathology has spurred interest in tyrosine kinase inhibitors (TKIs) as potential strategic therapeutic agents for AD. In the present study, we investigated whether the TKIs ibrutinib, PD180970, and cabozantinib, which have different on-targets, selectively regulate AD pathology in 3.5- to 4-month-old 5xFAD mice (a model of the early phase of AD). Ibrutinib (10 mg/kg, i.p.) effectively reduced amyloid-ß (Aß) plaque number, tau hyperphosphorylation and neuroinflammation in 5xFAD mice. Surprisingly, PD180970 (10 mg/kg, i.p.) did not alter Aß plaque number or neuroinflammatory responses and exacerbated tau hyperphosphorylation in 5xFAD mice. Cabozantinib (10 mg/kg, i.p.) had no effect on amyloidopathy but partially relieved tau hyperphosphorylation and astrogliosis. Taken together, our results suggest that not all TKIs have therapeutic effects on AD pathology in a mouse model of AD. Consequently, optimization of drug dosage, injection periods and administration routes should be considered when repurposing TKIs as novel AD therapeutics.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Enfermedades Neurodegenerativas
/
Enfermedad de Alzheimer
Límite:
Animals
Idioma:
En
Revista:
Mol Brain
Asunto de la revista:
BIOLOGIA MOLECULAR
/
CEREBRO
Año:
2023
Tipo del documento:
Article
Pais de publicación:
Reino Unido