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

Authors
Lee, Hyun-JuHwang, Jeong-WooPark, Jin-HeeJeong, Yoo JooJang, Ji-YeongHoe, Hyang-Sook
Issue Date
Aug-2023
Publisher
BioMed Central Ltd
Keywords
Alzheimer’s disease; Amyloid-β; Cabozantinib; Ibrutinib; Neuroinflammation; PD180970; Tau; Tyrosine kinase inhibitors.
Citation
Molecular Brain, v.16, no.1
Journal Title
Molecular Brain
Volume
16
Number
1
URI
http://scholarworks.bwise.kr/kbri/handle/2023.sw.kbri/973
DOI
10.1186/s13041-023-01051-9
ISSN
1756-6606
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.
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연구본부 (퇴행성뇌질환 연구그룹)
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