Pazopanib Reduces Phosphorylated Tau Levels and Alters Astrocytes in a Mouse Model of Tauopathy

Abstract

Hyperphosphorylation and aggregation of tau protein is a critical factor in many neurodegenerative diseases. These diseases are increasing in prevalence, and there are currently no cures. Previous work from our group and others has shown that tyrosine kinase inhibitors (TKIs) can stimulate autophagy, decrease pathological proteins, and improve symptoms in models of neurodegeneration. Here we examined the role of pazopanib in mouse models that express either human mutant P301L tau (TauP301L) or triple mutant amyloid precursor protein (3x-AβPP). The TauP301L mouse expresses P301L tau under the control of a prion promoter in both neurons and astrocytes, reminiscent of some human tauopathies. Pazopanib crosses the blood-brain barrier with no detectable peripheral off-side effects, and decreases p-tau in TauP301L mice. Pazopanib reaches a brain concentration sufficient for inhibition of several tyrosine kinases, including vascular endothelial growth factor receptors (VEGFRs). Further, pazopanib does not affect microglia but reduces astrocyte levels toward nontransgenic controls in TauP301L mice. Pazopanib does not alter amyloid beta levels or astrocytes in 3x-AβPP mice but modulates a number of inflammatory markers (IP-10, MIP-1α, MIP-1β, and RANTES). These data suggest that pazopanib may be involved in p-tau clearance and modulation of astrocytic activity in models of tauopathies.

Multikinase Abl/DDR/Src Inhibition Produces Optimal Effects for Tyrosine Kinase Inhibition in Neurodegeneration

“… Abl abelson, AUC area under the curve, C max maximum plasma concentration, DDR1/2 discoidin domain receptors 1 and 2, IC 50 half-maximal inhibitory concentration, PDGFR platelet-derived growth factor receptor, T max time to C max A [ 78 ] B [ 49 ] C [ 39 ] D [ 79 ] E [ 58 ] F [ 66 ] G [ 80 ] H [ 81 ] I [ 53 ] …”

“…However, bafetinib failed to alter the level of α-syn in transgenic PD models and affect dopamine metabolism using the same IP dose compared to either nilotinib or bosutinib, albeit bafetinib was reported to alter autophagy [ 57 ]. The half-maximal inhibitory concentration (IC 50 ) of bafetinib to Abl is 62 nM and 56 nM to PDGFRα [ 58 , 59 ] with no affinity to PDGFRβ [ 42 ]. Bafetinib (INNO-406) development was aimed at extending the susceptibility spectrum of mutations to TKIs and increasing selectivity towards Abl to reduce clinical adverse reactions during treatment, e.g., cardiovascular and metabolic toxicities of nilotinib [ 60 ].…”

Increased levels of Stress-inducible phosphoprotein-1 accelerates amyloid-β deposition in a mouse model of Alzheimer’s disease

“…1 and [29]) and C. elegans experiments showed that STI1 prevented Aβ toxicity in body wall muscle, we performed a number of assays to assess whether 3-5-month-old TgA-5xFAD mice present increased resilience to Aβ-toxicity. Firstly, we used the FD NeuroSilver staining kit, which labels degenerating neurons (axons and soma) [50,[63][64][65][66]. In the hippocampi of male mice, we found significantly more silver particles in TgA-5xFAD mice, compared to their 5xFAD controls (Fig.…”

Histone Deacetylase Inhibitor Alleviates the Neurodegenerative Phenotypes and Histone Dysregulation in Presenilins-Deficient Mice

“…Most notably, chemokine (C-C motif) ligand 4 (Ccl4) and S100a9 were found dramatically increased in the brain of cDKO mice, which were down-regulated by both environment enrichment and calorie restriction (Dong et al, 2007 ; Wu et al, 2008 ), while in our study, both genes were also down-regulated by NaB treatment. It has been shown that several AD-like mouse models with hyperphosphorylated tau and/or increased GFAP levels had significantly higher levels of Ccl4 (one of inflammatory markers, also known as MIP-1β; Dong et al, 2007 ; Javidnia et al, 2017 ), which might be a potential cerebrospinal fluid biomarker of AD (Trombetta et al, 2018 ). S100a9, as an inflammation-associated calcium binding protein, was proposed to participate in inflammatory-mediated events, intracellular calcium increase and iNOS generation contributing to neurodegeneration.…”