TY - JOUR
T1 - The diphenylpyrazole compound anle138b blocks Aβ channels and rescues disease phenotypes in a mouse model for amyloid pathology
AU - Martinez Hernandez, Ana
AU - Urbanke, Hendrik
AU - Gillman, Alan L.
AU - Lee, Joon
AU - Ryazanov, Sergey
AU - Agbemenyah, Hope Y.
AU - Benito, Eva
AU - Jain, Gaurav
AU - Kaurani, Lalit
AU - Grigorian, Gayane
AU - Leonov, Andrei
AU - Rezaei-Ghaleh, Nasrollah
AU - Wilken, Petra
AU - Arce, Fernando Teran
AU - Wagner, Jens
AU - Fuhrman, Martin
AU - Caruana, Mario
AU - Camilleri, Angelique
AU - Vassallo, Neville
AU - Zweckstetter, Markus
AU - Benz, Roland
AU - Giese, Armin
AU - Schneider, Anja
AU - Korte, Martin
AU - Lal, Ratnesh
AU - Griesinger, Christian
AU - Eichele, Gregor
AU - Fischer, Andre
N1 - Funding Information:
We thank Lina-Maria Jaime Tobonand Inga Urban for assistance. This work was supported by core funds from the DZNE (to AF, MZ, and MF), the Max Planck Society (to GE and CG), the Hans and Ilse Breuer Award for Alzheimer’s disease (to AF), the DFG project FI981/9-1 (to AF), the EU (ERC consolidator grant to AF), and the DFG (SFB803 project A04 to CG). HU holds a PhD fellowship from the Hans and Ilse Breuer Foundation. MF is supported by the CoEN Initiative CoEN3018 and the SFB1089 C01. NV is supported by the Malta Council for Science & Technology through the National Research & Innovation Programme (R&I-2008-068) and the University of Malta (PHBR06). AC was supported by the Malta Government Scholarship Scheme. J.L., A.L.G., and R.L. acknowledge support from the National Institute on Aging of National Institutes of Health (Grant AG028709).
Publisher Copyright:
© 2017 The Authors. Published under the terms of the CC BY 4.0 license
PY - 2018/1
Y1 - 2018/1
N2 - 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.
AB - 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.
KW - Alzheimer's disease
KW - Aβ channels
KW - amyloid pathology
KW - gene expression
KW - membrane pores
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U2 - 10.15252/emmm.201707825
DO - 10.15252/emmm.201707825
M3 - Article
C2 - 29208638
AN - SCOPUS:85037629631
SN - 1757-4676
VL - 10
SP - 32
EP - 47
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
IS - 1
ER -