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Reducing tau aggregates with anle138b delays disease progression in a mouse model of tauopathies

BIBLIOGRAPHIC THERAPEUTIC AGENT ANIMAL MODEL EXPERIMENTAL DESIGN OUTCOMES

Bibliographic

Year of Publication:
2015
Contact PI Name:
Martin Fuhrmann
Contact PI Affiliation:
German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Co-Authors:
Jens Wagner, Sybille Krauss, Song Shi, Sergey Ryazanov, Julia Steffen, Carolin Miklitz, Andrei Leonov, Alexander Kleinknecht, Bettina Göricke, Jochen H. Weishaupt, et al.,
Primary Reference (PubMED ID):
26439832
Funding Source:
Network of Centers of Excellence in Neurodegeneration (COEN)
European Union
Max Planck Society
Deutsche Forschungsgemeinschaft/German Research Foundation
Study Goal and Principal Findings:

The aim of this study was to test the efficacy of anle138b, small molecule with high bioavailability and low toxicity on tau aggregation in the human tau (P301S) transgenic mouse model.  Anle138b was administered orally from weaning to terminal disease, and examined both pathogenesis and survival. Anle138b was found to bind aggregated tau and inhibit tau aggregation in vitro and in vivo. Furthermore, anle138b treatment effectively ameliorated disease symptoms, increased survival time and improved cognition of tau transgenic PS19 mice. In addition, anle138b-treatment was associated with decreased synapse and neuron loss accompanied by a decreased gliosis in the hippocampus. In conclusion, these data suggest that inhibiting tau aggregation using small molecules represents a promising approach for the treatment of human tauopathies, and that anle138b might serve as a new lead for developing a disease-modifying therapy.

Bibliographic Notes:
Full Author List: Jens Wagner, Sybille Krauss, Song Shi, Sergey Ryazanov, Julia Steffen, Carolin Miklitz, Andrei Leonov, Alexander Kleinknecht, Bettina Göricke, Jochen H. Weishaupt, Daniel Weckbecker, Anne M. Reiner, Wolfgang Zinth, Johannes Levin, Dan Ehninger, Stefan Remy, Hans A. Kretzschmar, Christian Griesinger, Armin Giese, Martin Fuhrmann.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Small Molecule
Therapeutic Agent:
ANLE 138b
PubMed
PubChem
DrugBank
ClinicalTrials
Patents
Therapeutic Target:
Tau Protein
Open Targets
Pharos
Agora

Animal Model

Model Information:
Species:
Mouse
Model Type:
Tau
Model Name:
Tau P301S (Line PS19)
ALZFORUM
Strain/Genetic Background:
(C57BL/6 x C3H)F1

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
Behavioral
Open Field Test
Object Place Recognition
Prolonged Survival
Histopathology
Tau Pathology
Misfolded Tau
Activated Microglia
Neuronal Loss
Activated Astrocytes
Biochemical
phospho-Tau
Insoluble Tau
Autophagosomal Marker LC3-I
Autophagosomal Marker LC3-II
p62/Sequestosome 1 (SQSTM1)
phospho-Glycogen Synthase Kinase 3 beta (phospho-GSK3 beta)
Protein Phosphatase 2A (PP2A)
Aggregated Tau
Immunochemistry
Synaptic Density
Pharmacokinetics
Drug Concentration-Brain
Toxicology
Body Weight
Mortality
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