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 Fuhrman; Mario Caruana; Angelique Camilleri; Neville Vassallo; Markus Zweckstetter; Roland Benz; Armin Giese; Anja Schneider; Martin Korte; Ratnesh Lal; Christian Griesinger; Gregor Eichele; Andre Fischer

doi:10.15252/emmm.201707825

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 Fuhrman, Mario Caruana, Angelique Camilleri, Neville Vassallo, Markus ZweckstetterRoland Benz, Armin Giese, Anja Schneider, Martin Korte, Ratnesh Lal, Christian Griesinger, Gregor Eichele, Andre Fischer

Medicine

Research output: Contribution to journal › Article › peer-review

58 Scopus citations

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.

Original language	English (US)
Pages (from-to)	32-47
Number of pages	16
Journal	EMBO Molecular Medicine
Volume	10
Issue number	1
DOIs	https://doi.org/10.15252/emmm.201707825
State	Published - Jan 2018

Keywords

Alzheimer's disease
Aβ channels
amyloid pathology
gene expression
membrane pores

ASJC Scopus subject areas

Molecular Medicine

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10.15252/emmm.201707825

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Martinez Hernandez, A., Urbanke, H., Gillman, A. L., Lee, J., Ryazanov, S., Agbemenyah, H. Y., Benito, E., Jain, G., Kaurani, L., Grigorian, G., Leonov, A., Rezaei-Ghaleh, N., Wilken, P., Arce, F. T., Wagner, J., Fuhrman, M., Caruana, M., Camilleri, A., Vassallo, N., ... Fischer, A. (2018). The diphenylpyrazole compound anle138b blocks Aβ channels and rescues disease phenotypes in a mouse model for amyloid pathology. EMBO Molecular Medicine, 10(1), 32-47. https://doi.org/10.15252/emmm.201707825

Martinez Hernandez, A, Urbanke, H, Gillman, AL, Lee, J, Ryazanov, S, Agbemenyah, HY, Benito, E, Jain, G, Kaurani, L, Grigorian, G, Leonov, A, Rezaei-Ghaleh, N, Wilken, P, Arce, FT, Wagner, J, Fuhrman, M, Caruana, M, Camilleri, A, Vassallo, N, Zweckstetter, M, Benz, R, Giese, A, Schneider, A, Korte, M, Lal, R, Griesinger, C, Eichele, G & Fischer, A 2018, 'The diphenylpyrazole compound anle138b blocks Aβ channels and rescues disease phenotypes in a mouse model for amyloid pathology', EMBO Molecular Medicine, vol. 10, no. 1, pp. 32-47. https://doi.org/10.15252/emmm.201707825

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

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",

author = "{Martinez Hernandez}, Ana and Hendrik Urbanke and Gillman, {Alan L.} and Joon Lee and Sergey Ryazanov and Agbemenyah, {Hope Y.} and Eva Benito and Gaurav Jain and Lalit Kaurani and Gayane Grigorian and Andrei Leonov and Nasrollah Rezaei-Ghaleh and Petra Wilken and Arce, {Fernando Teran} and Jens Wagner and Martin Fuhrman and Mario Caruana and Angelique Camilleri and Neville Vassallo and Markus Zweckstetter and Roland Benz and Armin Giese and Anja Schneider and Martin Korte and Ratnesh Lal and Christian Griesinger and Gregor Eichele and Andre Fischer",

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year = "2018",

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doi = "10.15252/emmm.201707825",

language = "English (US)",

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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

PY - 2018/1

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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.

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KW - Aβ channels

KW - amyloid pathology

KW - gene expression

KW - membrane pores

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

Abstract

Keywords

ASJC Scopus subject areas

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