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The VEGF inhibitor vatalanib regulates AD pathology in 5xFAD mice
Seong Gak Jeon1, Hyun-Ju Lee1, HyunHee Park1
1Department of Neural Development and Disease, Korea Brain Research Institute (KBRI), 61, Cheomdan-ro, Dong-gu, Daegu, 41062, Republic of Korea.
Abstract:
Alzheimer's disease (AD) is a highly prevalent neurodegenerative disease characterized by Aβ accumulation and tau hyperphosphorylation. Epidemiological evidence for a negative correlation between cancer and AD has led to the proposed use of tyrosine kinase inhibitors (TKIs) such as dasatinib and masitinib for AD, with reported beneficial effects in the AD brain. The TKI vatalanib inhibits angiogenesis by inhibiting vascular endothelial growth factor receptor (VEGFR). Although changes in VEGF and VEGFR have been documented in AD, the effect of vatalanib on AD pathology has not been investigated. In this study, the effects of vatalanib on tau phosphorylation and Aβ accumulation in 5xFAD mice, a model of AD, were evaluated by immunohistochemistry. Vatalanib administration significantly reduced tau phosphorylation at AT8 and AT100 by increasing p-GSK-3β (Ser9) in 5xFAD mice. In addition, vatalanib reduced the number and area of Aβ plaques in the cortex in 5xFAD mice. Our results suggest that vatalanib has potential as a regulator of AD pathology.
Insights
Vatalanib, a tyrosine kinase inhibitor, shows promise in treating Alzheimer's disease (AD). This study found vatalanib reduces tau phosphorylation and amyloid-beta plaque accumulation in AD mouse models.
Area of Science:
- Neuroscience
- Pharmacology
- Biochemistry
Background:
- Alzheimer's disease (AD) is a prevalent neurodegenerative disorder marked by amyloid-beta (Aβ) and tau pathology.
- Epidemiological studies suggest a link between cancer and AD, leading to investigations into tyrosine kinase inhibitors (TKIs).
- Vatalanib, a TKI targeting VEGFR, has known anti-angiogenic properties, but its effect on AD pathology was unexplored.
Purpose of the Study:
- To investigate the therapeutic potential of vatalanib in an Alzheimer's disease mouse model.
- To evaluate vatalanib's impact on key AD pathological hallmarks: tau phosphorylation and Aβ accumulation.
Main Methods:
- Utilized the 5xFAD transgenic mouse model, a standard model for Alzheimer's disease research.
- Administered vatalanib to 5xFAD mice.
- Assessed tau phosphorylation and Aβ plaque burden using immunohistochemistry.
Main Results:
- Vatalanib treatment significantly decreased tau phosphorylation at AT8 and AT100 epitopes.
- This reduction in tau phosphorylation was associated with increased levels of phosphorylated GSK-3β (p-GSK-3β) at Serine 9.
- Vatalanib administration led to a significant reduction in both the number and area of cortical Aβ plaques.
Conclusions:
- Vatalanib demonstrates potential as a therapeutic agent for Alzheimer's disease.
- The drug effectively modulates key pathological pathways in AD, including tau phosphorylation and Aβ deposition.
- Further research into vatalanib's efficacy and safety for AD treatment is warranted.
