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

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.

Pubmed ID: 28869476 RIS Download

Mesh terms: Animals | Astrocytes | Calcium-Binding Proteins | Cell Line, Tumor | Cognition | Collagen Type IV | Cytokines | Disease Models, Animal | Dose-Response Relationship, Drug | Female | Glial Fibrillary Acidic Protein | Male | Mice | Mice, Inbred C57BL | Mice, Transgenic | Microfilament Proteins | Motor Activity | Mutation | Neuroblastoma | Phosphorylation | Pyrimidines | RNA, Small Interfering | Receptors, Vascular Endothelial Growth Factor | Silver Staining | Sulfonamides | Tauopathies | Transfection | Treatment Outcome | tau Proteins