The diphenylpyrazole compound anle138b blocks Aβ channels and rescues disease phenotypes in a mouse model for amyloid pathology

  • EMBO Mol Med. 2018 Jan;10(1):32-47. doi: 10.15252/emmm.201707825.
Ana Martinez Hernandez  1  2 ,  Hendrik Urbanke  1 ,  Alan L Gillman  3 ,  Joon Lee  3 ,  Sergey Ryazanov  4  5 ,  Hope Y Agbemenyah  6 ,  Eva Benito  1 ,  Gaurav Jain  1 ,  Lalit Kaurani  5 ,  Gayane Grigorian  7 ,  Andrei Leonov  4  5 ,  Nasrollah Rezaei-Ghaleh  4  8 ,  Petra Wilken  5  6  9 ,  Fernando Teran Arce  3 ,  Jens Wagner  10 ,  Martin Fuhrmann   #  10 ,  Mario Caruana  11 ,  Angelique Camilleri  11 ,  Neville Vassallo  11 ,  Markus Zweckstetter  4  5  8  12 ,  Roland Benz  13 ,  Armin Giese  14 ,  Anja Schneider  5  6  9 ,  Martin Korte  15  16 ,  Ratnesh Lal  17 ,  Christian Griesinger  18  5 ,  Gregor Eichele  19 ,  Andre Fischer  20  6
Affiliations
  • 1. Department for Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany.
  • 2. Department for Genes and Behavior, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
  • 3. 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.
  • 4. Department of NMR Based Structural Biology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
  • 5. DFG Research Center Nanoscale Microscopy and Molecular Physiology of the Brain, Göttingen, Germany.
  • 6. Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany.
  • 7. Department of Cellular Neurobiology, Technical University Braunschweig, Braunschweig, Germany.
  • 8. Department of Translational Structural Biology of Dementia, German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany.
  • 9. Group for Translational Research in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE) Göttingen, Göttingen, Germany.
  • 10. Group for Neuroimmunology and Imaging, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
  • 11. Department of Physiology and Biochemistry, Centre for Molecular Medicine and Biobanking, University of Malta, Msida, Malta.
  • 12. Department of Neurology, University Medical Center Göttingen, University of Göttingen, Göttingen, Germany.
  • 13. Life Sciences and Chemistry, Jacobs University of Bremen, Bremen, Germany.
  • 14. Center for Neuropathology and Prion Research, Ludwig-Maximilians-University Munich, Munich, Germany.
  • 15. Department of Cellular Neurobiology, Technical University Braunschweig, Braunschweig, Germany [email protected] [email protected] [email protected] [email protected] [email protected].
  • 16. Helmholtz Center for Infections Research, Braunschweig, Germany.
  • 17. 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 [email protected] [email protected] [email protected] [email protected] [email protected].
  • 18. Department of NMR Based Structural Biology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany [email protected] [email protected] [email protected] [email protected] [email protected].
  • 19. Department for Genes and Behavior, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany [email protected] [email protected] [email protected] [email protected] [email protected].
  • 20. Department for Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany [email protected] [email protected] [email protected] [email protected] [email protected].
  • # Contributed equally.
PMID: 29208638 DOI: 10.15252/emmm.201707825
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
Alzheimer's disease; Aβ channels; amyloid pathology; gene expression; membrane pores.
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