EMBO Molecular Medicine (Jan 2018)
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) Göttingen Germany
- Hendrik Urbanke
- Department for Epigenetics and Systems Medicine in Neurodegenerative Diseases German Center for Neurodegenerative Diseases (DZNE) Göttingen Germany
- 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 La Jolla CA USA
- 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 La Jolla CA USA
- Sergey Ryazanov
- Department of NMR Based Structural Biology Max Planck Institute for Biophysical Chemistry Göttingen Germany
- Hope Y Agbemenyah
- Department of Psychiatry and Psychotherapy University Medical Center Göttingen Göttingen Germany
- Eva Benito
- Department for Epigenetics and Systems Medicine in Neurodegenerative Diseases German Center for Neurodegenerative Diseases (DZNE) Göttingen Germany
- Gaurav Jain
- Department for Epigenetics and Systems Medicine in Neurodegenerative Diseases German Center for Neurodegenerative Diseases (DZNE) Göttingen Germany
- Lalit Kaurani
- DFG Research Center Nanoscale Microscopy and Molecular Physiology of the Brain Göttingen Germany
- Gayane Grigorian
- Department of Cellular Neurobiology Technical University Braunschweig Braunschweig Germany
- Andrei Leonov
- Department of NMR Based Structural Biology Max Planck Institute for Biophysical Chemistry Göttingen Germany
- Nasrollah Rezaei‐Ghaleh
- Department of NMR Based Structural Biology Max Planck Institute for Biophysical Chemistry Göttingen Germany
- Petra Wilken
- DFG Research Center Nanoscale Microscopy and Molecular Physiology of the Brain Göttingen Germany
- 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 La Jolla CA USA
- Jens Wagner
- Group for Neuroimmunology and Imaging German Center for Neurodegenerative Diseases (DZNE) Bonn Germany
- Martin Fuhrmann
- Group for Neuroimmunology and Imaging German Center for Neurodegenerative Diseases (DZNE) Bonn Germany
- Mario Caruana
- Department of Physiology and Biochemistry Centre for Molecular Medicine and Biobanking University of Malta Msida Malta
- Angelique Camilleri
- Department of Physiology and Biochemistry Centre for Molecular Medicine and Biobanking University of Malta Msida Malta
- Neville Vassallo
- Department of Physiology and Biochemistry Centre for Molecular Medicine and Biobanking University of Malta Msida Malta
- Markus Zweckstetter
- Department of NMR Based Structural Biology Max Planck Institute for Biophysical Chemistry Göttingen Germany
- Roland Benz
- Life Sciences and Chemistry Jacobs University of Bremen Bremen Germany
- Armin Giese
- Center for Neuropathology and Prion Research Ludwig‐Maximilians‐University Munich Munich Germany
- Anja Schneider
- DFG Research Center Nanoscale Microscopy and Molecular Physiology of the Brain Göttingen Germany
- Martin Korte
- Department of Cellular Neurobiology Technical University Braunschweig Braunschweig Germany
- 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 La Jolla CA USA
- Christian Griesinger
- Department of NMR Based Structural Biology Max Planck Institute for Biophysical Chemistry Göttingen Germany
- Gregor Eichele
- Department for Genes and Behavior Max Planck Institute for Biophysical Chemistry Göttingen Germany
- Andre Fischer
- Department for Epigenetics and Systems Medicine in Neurodegenerative Diseases German Center for Neurodegenerative Diseases (DZNE) Göttingen Germany
- 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
