Affiliations: [a] Department of Neurology, Laboratory for Dementiaand Parkinsonism, Translational Neurotherapeutics Program, Washington, DC, USA
| [b] Department of Pharmacologyand Physiology, Georgetown University Medical Center, Washington, DC, USA
Correspondence:
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Correspondence to: Charbel E-H. Moussa, Department of Neurology, Laboratory for Dementia and Parkinsonism, Translational Neurotherapeutics Program, 4000 Reservoir Rd. NW, Building D, Room 203-C, Washington, DC 20007-2145, USA. Tel.: +1 202 687 7328; Fax: +1 202 687 7378; E-mail: [email protected].
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.
