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

Alzheimer's disease (AD) is a neurodegenerative disease characterized by A beta 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-beta (A beta) plaque number, tau hyperphosphorylation and neuroinflammation in 5xFAD mice. Surprisingly, PD180970 (10 mg/kg, i.p.) did not alter A beta 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.

Automated summary

Alzheimer's disease (AD) is characterized by pathological features such as beta-amyloid deposition, tau hyperphosphorylation, neuroinflammation, and cognitive impairment. This study investigated the effects of three different tyrosine kinase inhibitors (TKIs) on AD pathology in a mouse model. The results showed that ibrutinib reduced beta-amyloid plaques, tau hyperphosphorylation, and neuroinflammation, while PD180970 exacerbated tau hyperphosphorylation and cabozantinib had limited effects. These findings suggest that not all TKIs have therapeutic effects on AD pathology, highlighting the importance of optimizing their use as novel AD therapeutics.