PUBLICATION
The GSK3β inhibitor, TDZD-8, rescues cognition in a zebrafish model of okadaic acid-induced Alzheimer's disease
- Authors
- Koehler, D., Shah, Z.A., Williams, F.E.
- ID
- ZDB-PUB-181106-18
- Date
- 2018
- Source
- Neurochemistry international 122: 31-37 (Journal)
- Registered Authors
- Williams, Fred
- Keywords
- Alzheimer's disease, GSK3β, Okadaic acid, PP2A, TDZD-8, Tau, Zebrafish
- MeSH Terms
-
- Alzheimer Disease/chemically induced
- Alzheimer Disease/drug therapy*
- Alzheimer Disease/metabolism
- Animals
- Brain/blood supply*
- Brain/metabolism
- Cognition/drug effects
- Disease Models, Animal
- Glycogen Synthase Kinase 3/genetics
- Glycogen Synthase Kinase 3/metabolism
- Glycogen Synthase Kinase 3 beta/metabolism
- Glycogen Synthase Kinase 3 beta/pharmacology*
- Neurons/drug effects
- Neurons/metabolism
- Okadaic Acid/pharmacology
- Thiadiazoles/pharmacology*
- Zebrafish
- tau Proteins/metabolism
- PubMed
- 30392874 Full text @ Neurochem. Int.
Citation
Koehler, D., Shah, Z.A., Williams, F.E. (2018) The GSK3β inhibitor, TDZD-8, rescues cognition in a zebrafish model of okadaic acid-induced Alzheimer's disease. Neurochemistry international. 122:31-37.
Abstract
Currently, no treatments exist that are able to directly treat against Alzheimer's disease (AD), and we are facing an inevitable increase in the near future of the amount of patients who will suffer from AD. Most animal models of AD are limited by not being able to recapitulate the entire pathology of AD. Recently an AD model in zebrafish was established by using the protein phosphatase 2A inhibitor, okadaic acid (OKA). Administering OKA to zebrafish was able to recapitulate most of the neuropathology associated with AD. Therefore, providing a drug discovery model for AD that is also time and cost efficient. This study was designed to investigate the effects of GSK3β inhibition by 4-benzyl-2-methyl-1, 2, 4-thiadiazolidine-3, 5-dione (TDZD-8) on this newly developed AD model. Fish were divided into 4 groups and each group received a different treatment. The fish were divided into a control group, a group treated with 1 μM TDZD-8 only, a group treated with 1 μM TDZD-8 + 100 nM OKA, and a group treated with 100 nM OKA only. Administering the GSK3β inhibitor to zebrafish concomitantly with OKA proved to be protective. TDZD-8 treatment reduced the mortality rate, the ratio of active: inactive GSK3β, pTau (Ser199), and restored PP2A activity. This further corroborates the use of GSKβ inhibitors in the treatment against AD and bolsters the use of the OKA-induced AD-like zebrafish model for drug discovery.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping