Rapamycin attenuates the progression of tau pathology in P301S tau transgenic mice


BIBLIOGRAPHIC THERAPEUTIC AGENT ANIMAL MODEL EXPERIMENTAL DESIGN OUTCOMES

Bibliographic

Year of Publication:
2013
Contact PI Name:
David Theo Winkler
Contact PI Affiliation:
Institute of Pathology, University Hospital Basel, Basel, Switzerland
Co-Authors:
S. Ozcelik, G. Fraser, P. Castets, V. Schaeffer, Z. Skachokova, K. Breu, F. Clavaguera, M. Sinnreich, L. Kappos, M. Goedert, M. Tolnay
Primary Reference (PubMED ID):
Funding Source:
Swiss National Science Foundation
Velux Foundation Switzerland
Study Goal and Principal Findings:

Altered autophagy contributes to the pathogenesis of Alzheimer's disease and other tauopathies, for which curative treatment options are still lacking. We have recently shown that trehalose reduces tau pathology in a tauopathy mouse model by stimulation of autophagy. Here, we studied the effect of the autophagy inducing drug rapamycin on the progression of tau pathology in P301S mutant tau transgenic mice. Rapamycin treatment resulted in a significant reduction in cortical tau tangles, less tau hyperphosphorylation, and lowered levels of insoluble tau in the forebrain. The favourable effect of rapamycin on tau pathology was paralleled by a qualitative reduction in astrogliosis. These effects were visible with early preventive or late treatment. We further noted an accumulation of the autophagy associated proteins p62 and LC3 in aged tangle bearing P301S mice that was lowered upon rapamycin treatment. Thus, rapamycin treatment defers the progression of tau pathology in a tauopathy animal model and autophagy stimulation may constitute a therapeutic approach for patients suffering from tauopathies.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Small Molecule
Therapeutic Agent:
Rapamycin (Rap)
Therapeutic Target:
Mechanistic Target of Rapamycin (mTOR)

Animal Model

Model Information:
Species:
Mouse
Model Type:
Tau
Strain/Genetic Background:
Not Reported

Experimental Design

Is the following information reported in the study?:
Power/Sample Size Calculation
Randomized into Groups
Blinded for Treatment
Blinded for Outcome Measures
Pharmacokinetic Measures
Pharmacodynamic Measures
Toxicology Measures
ADME Measures
Biomarkers
Dose
Formulation
Route of Delivery
Duration of Treatment
Frequency of Administration
Age of Animal at the Beginning of Treatment
Age of Animal at the End of Treatment
Sex as a Biological Variable
Study Balanced for Sex as a Biological Variable
Number of Premature Deaths
Number of Excluded Animals
Statistical Plan
Genetic Background
Inclusion/Exclusion Criteria Included
Conflict of Interest

Outcomes

Outcome Measured
Outcome Parameters
Histopathology
Tau Pathology
Neurofibrillary Tau Tangles
Activated Astrocytes
Biochemical
Insoluble Tau
phospho-Tau
Autophagosomal Marker LC3-I
p62/Sequestosome 1 (SQSTM1)
Soluble Tau
Mechanistic Target of Rapamycin (mTOR)
Autophagosomal Marker LC3-II
S6-Ribosomal Protein
phospho-S6-Ribosomal Protein
Immunochemistry
Glial Fibrillary Acidic Protein (GFAP)
phospho-Tau
Activated Astrocytes
NFT Tau
Microscopy
Stereology
Pharmacokinetics
Drug Concentration-Brain
Blood Brain Barrier Penetration
Drug Concentration-Blood
Pharmacodynamics
Target Engagement (Inhibition Mechanistic Target of Rapamycin)

Source URL: http://alzped.nia.nih.gov/rapamycin-attenuates