The VEGF inhibitor vatalanib regulates AD pathology in 5xFAD mice
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The VEGF inhibitor vatalanib regulates AD pathology in 5xFAD mice Seong Gak Jeon, Hyun‑ju Lee, HyunHee Park, Kyung‑Min Han and Hyang‑Sook Hoe*
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 benefi‑ cial 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 accumula‑ tion 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. Keywords: Alzheimer’s disease, Tau, Amyloid beta, 5xFAD mice, Vatalanib, Vascular endothelial growth factor, Tyrosine kinase inhibitor Alzheimer’s disease (AD) is the most common progressive neurodegenerative disease. The accumulation of amyloid β (Aβ) plaques and neurofibrillary tangles (NFTs) in the brain is the neuropathological hallmark of AD. Aβ plaques are formed from the accumulation of Aβ produced by sequential cleavage of amyloid precursor protein (APP) via β- and γ-secretase, and NFTs are aggregates of hyperphosphorylated tau, which normally functions in microtubule stabilization. Aβ plaque and NFT levels are both discriminators of and contributors to AD progression and are closely correlated with cognitive impairment in AD subjects [1]. Although AD and cancer share aging as a common factor, accumulating epidemiological evidence indicates a negative correlation between cancer and AD. This evidence has led to the proposed repurposing of cancer drugs of various mechanisms of *Correspondence: [email protected] Department of Neural Development and Disease, Korea Brain Research Institute (KBRI), 61, Cheomdan‑ro, Dong‑gu, Daegu 41062, Republic of Korea
action for the treatment of AD [2]. These cancer drugs include tyrosine kinase inhibitors (TKIs) such as dasatinib, masitinib, and imatinib, which have been shown to have therapeutic effects on the pathogenesis of AD [3–5]. Vatalanib, a small-molecule anticancer drug that inhibits angiogenesis (Fig. 1a), is a broad-spectrum TKI that exerts its effects by occupying the ATP-binding sites of vascular endothelial growth factor receptor 1–3 (VEGFR1–3), platelet-derived growth factor receptor α (PDGFRα), and c-KIT [6]. VEGF and VEGFR have been implicated in angiogenesis as well as blood–brain-barrier (BBB) permeability and microglial chemotaxis
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