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

Abstract

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 (10 mg/kg, i.p.) effectively reduced amyloid-β (Aβ) plaque number, tau hyperphosphorylation and neuroinflammation in 5xFAD mice. Surprisingly, PD180970 (10 mg/kg, i.p.) did not alter Aβ 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.

Combining supervised and unsupervised analyses to quantify behavioral phenotypes and validate therapeutic efficacy in a triple transgenic mouse model of Alzheimer’s disease

“…It is often prescribed to treat medullary thyroid cancer and some kidney and liver cancers. A recent study found that cabozantinib partially reduced tau hyperphosphorylation and astrogliosis in 5xFAD mice 28 . Protein kinase inhibitors have been previously proposed as candidates for AD treatment due to their autophagy modulation properties 29 .…”

Evaluation of altered cell-cell communication between glia and neurons in the hippocampus of 3xTg-AD mice at two time points

“…Finally, we found that FEA terms of predicted targets were associated with signaling pathways at both time points, but 12-month targets included terms of signaling regulation through protein and tyrosine kinase activity. Since predicted targets at 12 months are associated with protein and tyrosine kinase activity in neurons and tyrosine kinase inhibitors, have been investigated as potential therapeutics, 86 the interactions we predicted may produce novel therapeutic targets for drug repurposing or discovery.…”