Inhibiting tyrosine kinase c‐KIT as a therapeutic strategy for Alzheimer's Disease. (20th December 2022) - Stevenson, Max E
Abstract: Background: Impaired autophagy and neuroinflammation, two primary features of Alzheimer's Disease, were examined as potential pharmacological targets for alleviating amyloid‐beta and tau burden using novel tyrosine kinase inhibitors. Method: Transgenic APP mice were treated for 6 weeks with either one of two novel tyrosine kinase inhibitors or DMSO (n = 10) before having their behavior tested on the novel object recognition test, the Morris water maze, and the elevated plus maze. Brain samples were then extracted and probed for levels of amyloid‐beta, tau, and autophagic machinery, as well as numbers of mast cells and microglia using ELISA, immunohistochemistry, and flow cytometry. Result: Mice treated with our novel tyrosine kinase inhibitors exhibited robust improvements on behavioral measures. These treated mice displayed concurrent decreases in levels of amyloid‐beta and tau, as well as increased levels of autophagic machinery and decreased numbers of microglia and mast cells. Conclusion: Tyrosine kinase inhibition represents a valid mechanism for improving autophagic clearance of neurotoxic protein and mitigating mast cell and microglial‐mediated inflammation, identifying this method as a potential target for therapeutic intervention for treating Alzheimer's Disease.