The Streptomyces metabolite anhydroexfoliamycin ameliorates hallmarks of Alzheimer’s disease in vitro and in vivo

M. Leiros; E. Alonso; M. E. Rateb; R. Ebel; M. Jaspars; A. Alfonso; L. M. Botana

doi:10.1016/j.neuroscience.2015.07.082

The Streptomyces metabolite anhydroexfoliamycin ameliorates hallmarks of Alzheimer’s disease in vitro and in vivo

M. Leiros, E. Alonso, M. E. Rateb, R. Ebel, M. Jaspars, A. Alfonso, L. M. Botana^*

^*Corresponding author for this work

Chemistry

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

30 Citations (Scopus)

Abstract

Anhydroexfoliamycin (1) and undecylprodigiosin (2) have been previously described as neuroprotective molecules against oxidative stress in neurons. Since oxidative stress is strongly correlated with neurodegenerative diseases, we have evaluated their effects over the principal hallmarks of Alzheimer's disease (AD). Both compounds were tested in vitro in two different neuroblastoma cellular models, one for amyloid precursor protein metabolism studies (BE(2)-M17) and another one specific for taupathology in AD (SH-SY5Y-TMHT441). Amyloid-beta (A beta) levels, beta-secretase (BACE1) activity, tau phosphorylation, extracellular signal-regulated kinase (ERK) and glycogen synthase kinase-3beta (GSK3 beta) expression were analyzed and while undecylprodigiosin (2) produced poor results, anhydroexfoliamycin (1) strongly inhibited GSK3 beta, reducing tau phosphorylation in vitro (0.1 mu M). A competitive assay of anhydroexfoliamycin (1) and the specific c-Jun N-terminal kinase (JNK) inhibitor, SP600125, showed that the reduction of the phosphorylated tau levels is mediated by the JNK pathway in SH-SY5Y-TMHT441 cells. Thus, this compound was tested in vivo by intraperitoneal administration in 3xTg-AD mice, confirming the positive results registered in the in vitro assays. This work presents anhydroexfoliamycin (1) as a promising candidate for further studies in drug development against neurodegenerative diseases. (C) 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

Original language	English
Pages (from-to)	26-35
Number of pages	10
Journal	Neuroscience
Volume	305
Early online date	3 Aug 2015
DOIs	https://doi.org/10.1016/j.neuroscience.2015.07.082
Publication status	Published - 1 Oct 2015

Bibliographical note

Acknowledgments
The research leading to these results has received funding from the following FEDER cofunded-grants: from CDTI and Technological Funds, supported by Ministerio de Economía y Competitividad, AGL2012-40185-CO2-01 and Consellería de Cultura, Educación e Ordenación Universitaria, GRC2013-016, and through Axencia Galega de Innovación, Spain, ITC-20133020 SINTOX, IN852A 2013/16-3 MYTIGAL; from CDTI under ISIP Programme, Spain, IDI-20130304 APTAFOOD; from the European Union’s Seventh Framework Programme managed by REA – Research Executive Agency (FP7/2007-2013) under grant agreement Nos. 265409 μAQUA, 315285 CIGUATOOLS and 312184 PHARMASEA.

We acknowledge the contribution of the Institute of Applied Science at the University of the South Pacific in Suva, Fiji for assistance in the collection of the sponge material. The Scottish University Life Science Alliance is acknowledged for their funding of the Marine Biodiscovery Centre Compound Library. We thank Dr Gimenez-Llort and Dr Laferla for providing the 3xTg-AD mice.

Keywords

N-TERMINAL KINASE
TAU-PROTEIN
SYNAPTIC DYSFUNCTION
HYPOTHESIS
THERAPY
MODEL
BETA
THERAPEUTICS
PATHWAYS

Access to Document

10.1016/j.neuroscience.2015.07.082Licence: Unspecified

Cite this

@article{448126bac17045788e40088ef0c4e4b8,

title = "The Streptomyces metabolite anhydroexfoliamycin ameliorates hallmarks of Alzheimer{\textquoteright}s disease in vitro and in vivo",

abstract = "Anhydroexfoliamycin (1) and undecylprodigiosin (2) have been previously described as neuroprotective molecules against oxidative stress in neurons. Since oxidative stress is strongly correlated with neurodegenerative diseases, we have evaluated their effects over the principal hallmarks of Alzheimer's disease (AD). Both compounds were tested in vitro in two different neuroblastoma cellular models, one for amyloid precursor protein metabolism studies (BE(2)-M17) and another one specific for taupathology in AD (SH-SY5Y-TMHT441). Amyloid-beta (A beta) levels, beta-secretase (BACE1) activity, tau phosphorylation, extracellular signal-regulated kinase (ERK) and glycogen synthase kinase-3beta (GSK3 beta) expression were analyzed and while undecylprodigiosin (2) produced poor results, anhydroexfoliamycin (1) strongly inhibited GSK3 beta, reducing tau phosphorylation in vitro (0.1 mu M). A competitive assay of anhydroexfoliamycin (1) and the specific c-Jun N-terminal kinase (JNK) inhibitor, SP600125, showed that the reduction of the phosphorylated tau levels is mediated by the JNK pathway in SH-SY5Y-TMHT441 cells. Thus, this compound was tested in vivo by intraperitoneal administration in 3xTg-AD mice, confirming the positive results registered in the in vitro assays. This work presents anhydroexfoliamycin (1) as a promising candidate for further studies in drug development against neurodegenerative diseases. (C) 2015 IBRO. Published by Elsevier Ltd. All rights reserved.",

keywords = "N-TERMINAL KINASE, TAU-PROTEIN, SYNAPTIC DYSFUNCTION, HYPOTHESIS, THERAPY, MODEL, BETA, THERAPEUTICS, PATHWAYS",

author = "M. Leiros and E. Alonso and Rateb, {M. E.} and R. Ebel and M. Jaspars and A. Alfonso and Botana, {L. M.}",

note = "Acknowledgments The research leading to these results has received funding from the following FEDER cofunded-grants: from CDTI and Technological Funds, supported by Ministerio de Econom{\'i}a y Competitividad, AGL2012-40185-CO2-01 and Conseller{\'i}a de Cultura, Educaci{\'o}n e Ordenaci{\'o}n Universitaria, GRC2013-016, and through Axencia Galega de Innovaci{\'o}n, Spain, ITC-20133020 SINTOX, IN852A 2013/16-3 MYTIGAL; from CDTI under ISIP Programme, Spain, IDI-20130304 APTAFOOD; from the European Union{\textquoteright}s Seventh Framework Programme managed by REA – Research Executive Agency (FP7/2007-2013) under grant agreement Nos. 265409 μAQUA, 315285 CIGUATOOLS and 312184 PHARMASEA. We acknowledge the contribution of the Institute of Applied Science at the University of the South Pacific in Suva, Fiji for assistance in the collection of the sponge material. The Scottish University Life Science Alliance is acknowledged for their funding of the Marine Biodiscovery Centre Compound Library. We thank Dr Gimenez-Llort and Dr Laferla for providing the 3xTg-AD mice.",

year = "2015",

month = oct,

day = "1",

doi = "10.1016/j.neuroscience.2015.07.082",

language = "English",

volume = "305",

pages = "26--35",

journal = "Neuroscience",

issn = "0306-4522",

publisher = "Elsevier Limited",

}

TY - JOUR

T1 - The Streptomyces metabolite anhydroexfoliamycin ameliorates hallmarks of Alzheimer’s disease in vitro and in vivo

AU - Leiros, M.

AU - Alonso, E.

AU - Rateb, M. E.

AU - Ebel, R.

AU - Jaspars, M.

AU - Alfonso, A.

AU - Botana, L. M.

N1 - Acknowledgments The research leading to these results has received funding from the following FEDER cofunded-grants: from CDTI and Technological Funds, supported by Ministerio de Economía y Competitividad, AGL2012-40185-CO2-01 and Consellería de Cultura, Educación e Ordenación Universitaria, GRC2013-016, and through Axencia Galega de Innovación, Spain, ITC-20133020 SINTOX, IN852A 2013/16-3 MYTIGAL; from CDTI under ISIP Programme, Spain, IDI-20130304 APTAFOOD; from the European Union’s Seventh Framework Programme managed by REA – Research Executive Agency (FP7/2007-2013) under grant agreement Nos. 265409 μAQUA, 315285 CIGUATOOLS and 312184 PHARMASEA. We acknowledge the contribution of the Institute of Applied Science at the University of the South Pacific in Suva, Fiji for assistance in the collection of the sponge material. The Scottish University Life Science Alliance is acknowledged for their funding of the Marine Biodiscovery Centre Compound Library. We thank Dr Gimenez-Llort and Dr Laferla for providing the 3xTg-AD mice.

PY - 2015/10/1

Y1 - 2015/10/1

N2 - Anhydroexfoliamycin (1) and undecylprodigiosin (2) have been previously described as neuroprotective molecules against oxidative stress in neurons. Since oxidative stress is strongly correlated with neurodegenerative diseases, we have evaluated their effects over the principal hallmarks of Alzheimer's disease (AD). Both compounds were tested in vitro in two different neuroblastoma cellular models, one for amyloid precursor protein metabolism studies (BE(2)-M17) and another one specific for taupathology in AD (SH-SY5Y-TMHT441). Amyloid-beta (A beta) levels, beta-secretase (BACE1) activity, tau phosphorylation, extracellular signal-regulated kinase (ERK) and glycogen synthase kinase-3beta (GSK3 beta) expression were analyzed and while undecylprodigiosin (2) produced poor results, anhydroexfoliamycin (1) strongly inhibited GSK3 beta, reducing tau phosphorylation in vitro (0.1 mu M). A competitive assay of anhydroexfoliamycin (1) and the specific c-Jun N-terminal kinase (JNK) inhibitor, SP600125, showed that the reduction of the phosphorylated tau levels is mediated by the JNK pathway in SH-SY5Y-TMHT441 cells. Thus, this compound was tested in vivo by intraperitoneal administration in 3xTg-AD mice, confirming the positive results registered in the in vitro assays. This work presents anhydroexfoliamycin (1) as a promising candidate for further studies in drug development against neurodegenerative diseases. (C) 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

AB - Anhydroexfoliamycin (1) and undecylprodigiosin (2) have been previously described as neuroprotective molecules against oxidative stress in neurons. Since oxidative stress is strongly correlated with neurodegenerative diseases, we have evaluated their effects over the principal hallmarks of Alzheimer's disease (AD). Both compounds were tested in vitro in two different neuroblastoma cellular models, one for amyloid precursor protein metabolism studies (BE(2)-M17) and another one specific for taupathology in AD (SH-SY5Y-TMHT441). Amyloid-beta (A beta) levels, beta-secretase (BACE1) activity, tau phosphorylation, extracellular signal-regulated kinase (ERK) and glycogen synthase kinase-3beta (GSK3 beta) expression were analyzed and while undecylprodigiosin (2) produced poor results, anhydroexfoliamycin (1) strongly inhibited GSK3 beta, reducing tau phosphorylation in vitro (0.1 mu M). A competitive assay of anhydroexfoliamycin (1) and the specific c-Jun N-terminal kinase (JNK) inhibitor, SP600125, showed that the reduction of the phosphorylated tau levels is mediated by the JNK pathway in SH-SY5Y-TMHT441 cells. Thus, this compound was tested in vivo by intraperitoneal administration in 3xTg-AD mice, confirming the positive results registered in the in vitro assays. This work presents anhydroexfoliamycin (1) as a promising candidate for further studies in drug development against neurodegenerative diseases. (C) 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

KW - N-TERMINAL KINASE

KW - TAU-PROTEIN

KW - SYNAPTIC DYSFUNCTION

KW - HYPOTHESIS

KW - THERAPY

KW - MODEL

KW - BETA

KW - THERAPEUTICS

KW - PATHWAYS

U2 - 10.1016/j.neuroscience.2015.07.082

DO - 10.1016/j.neuroscience.2015.07.082

M3 - Article

SN - 0306-4522

VL - 305

SP - 26

EP - 35

JO - Neuroscience

JF - Neuroscience

ER -

The Streptomyces metabolite anhydroexfoliamycin ameliorates hallmarks of Alzheimer’s disease in vitro and in vivo

Abstract

Bibliographical note

Keywords

Access to Document

Fingerprint

Cite this