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Pazopanib Reduces Phosphorylated Tau Levels and Alters Astrocytes in a Mouse Model of Tauopathy
Monica Javidnia1,2, Michaeline L Hebron1, Yue Xin1
1Department of Neurology, Laboratory for Dementiaand Parkinsonism, Translational Neurotherapeutics Program, Washington, DC, USA.
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.
Insights
Pazopanib, a tyrosine kinase inhibitor, reduces pathological tau protein in mouse models of tauopathies. This drug may aid in clearing phosphorylated tau and modulating astrocyte activity, offering potential therapeutic avenues for neurodegenerative diseases.
Area of Science:
- Neuroscience
- Pharmacology
Background:
- Hyperphosphorylation and aggregation of tau protein are key factors in neurodegenerative diseases.
- Current treatments for these diseases are limited, highlighting the need for novel therapeutic strategies.
Purpose of the Study:
- To investigate the efficacy of pazopanib, a tyrosine kinase inhibitor (TKI), in mouse models of tauopathies and amyloid precursor protein mutations.
- To assess pazopanib's effects on pathological tau protein, amyloid beta, astrocyte activity, and inflammatory markers.
Main Methods:
- Utilized mouse models expressing human mutant P301L tau (TauP301L) and triple mutant amyloid precursor protein (3x-AβPP).
- Administered pazopanib and evaluated its effects on brain concentrations, p-tau levels, amyloid beta, microglia, astrocytes, and inflammatory markers.
Main Results:
- Pazopanib effectively reduced phosphorylated tau (p-tau) in TauP301L mice and crossed the blood-brain barrier with no peripheral side effects.
- Pazopanib modulated inflammatory markers in 3x-AβPP mice but did not alter amyloid beta levels.
- Pazopanib reduced astrocyte levels in TauP301L mice without affecting microglia.
Conclusions:
- Pazopanib demonstrates potential in reducing pathological tau and modulating astrocytic activity in tauopathy models.
- These findings suggest pazopanib as a potential therapeutic agent for tauopathies and related neurodegenerative conditions.
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