Back to Search
Start Over
An inhibitor with GSK3β and DYRK1A dual inhibitory properties reduces Tau hyperphosphorylation and ameliorates disease in models of Alzheimer's disease.
- Source :
-
Neuropharmacology . Jul2023, Vol. 232, pN.PAG-N.PAG. 1p. - Publication Year :
- 2023
-
Abstract
- Since Alzheimer's disease (AD) is a complex and multifactorial neuropathology, the discovery of multi-targeted inhibitors has gradually demonstrated greater therapeutic potential. Neurofibrillary tangles (NFTs), the main neuropathologic hallmarks of AD, are mainly associated with hyperphosphorylation of the microtubule-associated protein Tau. The overexpression of GSK3β and DYRK1A has been recognized as an important contributor to hyperphosphorylation of Tau, leading to the strategy of using dual-targets inhibitors for the treatment of this disorder. ZDWX-12 and ZDWX-25, as harmine derivatives, were found good inhibition on dual targets in our previous study. Here, we firstly evaluated the inhibition effect of Tau hyperphosphorylation using two compounds by HEK293-Tau P301L cell-based model and okadaic acid (OKA)-induced mouse model. We found that ZDWX-25 was more effective than ZDWX-12. Then, based on comprehensively investigations on ZDWX-25 in vitro and in vivo, 1) the capability of ZDWX-25 to show a reduction in phosphorylation of multiple Tau epitopes in OKA-induced neurodegeneration cell models, and 2) the effect of reduction on NFTs by 3xTg-AD mouse model under administration of ZDWX-25, an orally bioavailable, brain-penetrant dual-targets inhibitor with low toxicity. Our data highlight that ZDWX-25 is a promising drug for treating AD. • The effects of ZDWX-25 had been investigated for the first time in several models of Tau hyperphosphorylation. • ZDWX-25 reduced the formation of NFTs in 3×Tg AD mice and thus improving cognitive function in model AD mice. • ZDWX-25 had good BBB permeability, good PK properties and low toxic effects, and it was a promising anti-AD drug. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00283908
- Volume :
- 232
- Database :
- Academic Search Index
- Journal :
- Neuropharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 163225466
- Full Text :
- https://doi.org/10.1016/j.neuropharm.2023.109525