Profiling tyrosine kinase inhibitors as AD therapeutics in a mouse model of AD

초록

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by Aβ 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 effectively reduced amyloid- (Aβ) plaque number, tau hyperphosphorylation and neuroinflammation in 5xFAD mice. Surprisingly, PD180970 did not alter A plaque number or neuroinflammatory responses and exacerbated tau hyperphosphorylation in 5xFAD mice. Cabozantinib 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. Consequently, optimization of drug dosage, injection periods and administration routes should be considered when repurposing TKIs as novel AD therapeutics.