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

Molecular Brain

Micro Report

Jeong-Woo Hwang¹  Ji-Yeong Jang¹  Hyun-ju Lee¹  Jin-Hee Park²  Hyang-Sook Hoe²  Yoo Joo Jeong² 

[1] Department of Neural Development and Disease, Korea Brain Research Institute (KBRI), 61, Cheomdan-ro, 41068, Daegu, Republic of Korea;Department of Neural Development and Disease, Korea Brain Research Institute (KBRI), 61, Cheomdan-ro, 41068, Daegu, Republic of Korea;Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology, 42988, Daegu, Republic of Korea;

关键词: Alzheimer’s disease;    Tyrosine kinase inhibitors;    Amyloid-β;    Tau;    Neuroinflammation;    Ibrutinib;    PD180970;    Cabozantinib;   

DOI  :  10.1186/s13041-023-01051-9

 received in 2023-06-18, accepted in 2023-08-04,  发布年份 2023

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY   
© Min Zhuo, Bong-Kiun Kaang and BioMed central Ltd. 2023

【 图 表 】

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