EMBO Molecular Medicine (Dec 2017)
The diphenylpyrazole compound anle138b blocks Aβ channels and rescues disease phenotypes in a mouse model for amyloid pathology
- Ana Martinez Hernandez,
- Hendrik Urbanke,
- Alan L Gillman,
- Joon Lee,
- Sergey Ryazanov,
- Hope Y Agbemenyah,
- Eva Benito,
- Gaurav Jain,
- Lalit Kaurani,
- Gayane Grigorian,
- Andrei Leonov,
- Nasrollah Rezaei‐Ghaleh,
- Petra Wilken,
- Fernando Teran Arce,
- Jens Wagner,
- Martin Fuhrmann,
- Mario Caruana,
- Angelique Camilleri,
- Neville Vassallo,
- Markus Zweckstetter,
- Roland Benz,
- Armin Giese,
- Anja Schneider,
- Martin Korte,
- Ratnesh Lal,
- Christian Griesinger,
- Gregor Eichele,
- Andre Fischer
Affiliations
- Ana Martinez Hernandez
- Department for Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE)
- Hendrik Urbanke
- Department for Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE)
- Alan L Gillman
- Department of Bioengineering, Materials Science and Engineering, Department of Mechanical and Aerospace Engineering and Institute of Engineering in Medicine, University of California San Diego
- Joon Lee
- Department of Bioengineering, Materials Science and Engineering, Department of Mechanical and Aerospace Engineering and Institute of Engineering in Medicine, University of California San Diego
- Sergey Ryazanov
- Department of NMR Based Structural Biology, Max Planck Institute for Biophysical Chemistry
- Hope Y Agbemenyah
- Department of Psychiatry and Psychotherapy, University Medical Center Göttingen
- Eva Benito
- Department for Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE)
- Gaurav Jain
- Department for Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE)
- Lalit Kaurani
- DFG Research Center Nanoscale Microscopy and Molecular Physiology of the Brain
- Gayane Grigorian
- Department of Cellular Neurobiology, Technical University Braunschweig
- Andrei Leonov
- Department of NMR Based Structural Biology, Max Planck Institute for Biophysical Chemistry
- Nasrollah Rezaei‐Ghaleh
- Department of NMR Based Structural Biology, Max Planck Institute for Biophysical Chemistry
- Petra Wilken
- DFG Research Center Nanoscale Microscopy and Molecular Physiology of the Brain
- Fernando Teran Arce
- Department of Bioengineering, Materials Science and Engineering, Department of Mechanical and Aerospace Engineering and Institute of Engineering in Medicine, University of California San Diego
- Jens Wagner
- Group for Neuroimmunology and Imaging, German Center for Neurodegenerative Diseases (DZNE)
- Martin Fuhrmann
- Group for Neuroimmunology and Imaging, German Center for Neurodegenerative Diseases (DZNE)
- Mario Caruana
- Department of Physiology and Biochemistry, Centre for Molecular Medicine and Biobanking, University of Malta
- Angelique Camilleri
- Department of Physiology and Biochemistry, Centre for Molecular Medicine and Biobanking, University of Malta
- Neville Vassallo
- Department of Physiology and Biochemistry, Centre for Molecular Medicine and Biobanking, University of Malta
- Markus Zweckstetter
- Department of NMR Based Structural Biology, Max Planck Institute for Biophysical Chemistry
- Roland Benz
- Life Sciences and Chemistry, Jacobs University of Bremen
- Armin Giese
- Center for Neuropathology and Prion Research, Ludwig‐Maximilians‐University Munich
- Anja Schneider
- DFG Research Center Nanoscale Microscopy and Molecular Physiology of the Brain
- Martin Korte
- Department of Cellular Neurobiology, Technical University Braunschweig
- Ratnesh Lal
- Department of Bioengineering, Materials Science and Engineering, Department of Mechanical and Aerospace Engineering and Institute of Engineering in Medicine, University of California San Diego
- Christian Griesinger
- Department of NMR Based Structural Biology, Max Planck Institute for Biophysical Chemistry
- Gregor Eichele
- Department for Genes and Behavior, Max Planck Institute for Biophysical Chemistry
- Andre Fischer
- Department for Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE)
- DOI
- https://doi.org/10.15252/emmm.201707825
- Journal volume & issue
-
Vol. 10,
no. 1
pp. 32 – 47
Abstract
Abstract Alzheimer's disease is a devastating neurodegenerative disease eventually leading to dementia. An effective treatment does not yet exist. Here we show that oral application of the compound anle138b restores hippocampal synaptic and transcriptional plasticity as well as spatial memory in a mouse model for Alzheimer's disease, when given orally before or after the onset of pathology. At the mechanistic level, we provide evidence that anle138b blocks the activity of conducting Aβ pores without changing the membrane embedded Aβ‐oligomer structure. In conclusion, our data suggest that anle138b is a novel and promising compound to treat AD‐related pathology that should be investigated further.
Keywords
