Pohland 2016 Neurochem Res: Difference between revisions
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{{Publication | {{Publication | ||
|title=Pohland M, Hagl S, Pellowska M, Wurglics M, Schubert-Zsilavecz M, Eckert GP (2016) MH84: a novel γ-secretase modulator/PPARγ agonist-improves mitochondrial dysfunction in a cellular model of Alzheimer's disease. Neurochem Res 41:231-42. | |title=Pohland M, Hagl S, Pellowska M, Wurglics M, Schubert-Zsilavecz M, Eckert GP (2016) MH84: a novel γ-secretase modulator/PPARγ agonist-improves mitochondrial dysfunction in a cellular model of Alzheimer's disease. Neurochem Res 41:231-42. | ||
|info=[https://www.ncbi.nlm.nih.gov/pubmed/26721513 PMID: 26721513] | |info=[https://www.ncbi.nlm.nih.gov/pubmed/26721513 PMID: 26721513] | ||
|authors=Pohland M, Hagl S, Pellowska M, Wurglics M, Schubert-Zsilavecz M, Eckert GP | |authors=Pohland M, Hagl S, Pellowska M, Wurglics M, Schubert-Zsilavecz M, Eckert GP | ||
|year=2016 | |year=2016 | ||
|journal=Neurochem Res | |journal=Neurochem Res | ||
|abstract=Developing new therapeutic strategies for Alzheimer's disease (AD) is a current challenge. Approved drugs merely act symptomatically and delay the progression of the disease for a relatively short period of time. Here, we investigated the effectiveness of MH84 in a cellular HEK293<sub>APPwt</sub> model of AD, characterized by elevated beta amyloid protein levels (Aβ1-42) and mitochondrial dysfunction. MH84 is a derivate of pirinixic acid belonging to a novel class of γ-secretase modulators, which combines γ-secretase modulation with activation of peroxisome proliferator-activator receptor gamma (PPARγ). The mitochondria modifying Dimebon, the γ-secretase blocker DAPT, and the PPARγ agonist pioglitazone were used as controls. MH84 protects against nitrosative stress, increased mitochondrial respiration, citrate synthase (CS) activity and protein levels of PGC1α indicating enhanced mitochondrial content at nano-molar concentrations. Concurrently, MH84 decreased protein levels of APP, Aβ1-42, and C-terminal fragments at micro-molar concentrations. Both Dimebon and DAPT reduced cellular Aβ1-42 levels. Dimebon improved mitochondrial functions and DAPT decreased mitochondrial membrane potential. Pioglitazone had no effects on APP processing and mitochondrial function. Our data emphasizes MH84 as possible novel therapeutic agent with mitochondria-based mode of action. | |abstract=Developing new therapeutic strategies for Alzheimer's disease (AD) is a current challenge. Approved drugs merely act symptomatically and delay the progression of the disease for a relatively short period of time. Here, we investigated the effectiveness of MH84 in a cellular HEK293<sub>APPwt</sub> model of AD, characterized by elevated beta amyloid protein levels (Aβ1-42) and mitochondrial dysfunction. MH84 is a derivate of pirinixic acid belonging to a novel class of γ-secretase modulators, which combines γ-secretase modulation with activation of peroxisome proliferator-activator receptor gamma (PPARγ). The mitochondria modifying Dimebon, the γ-secretase blocker DAPT, and the PPARγ agonist pioglitazone were used as controls. MH84 protects against nitrosative stress, increased mitochondrial respiration, citrate synthase (CS) activity and protein levels of PGC1α indicating enhanced mitochondrial content at nano-molar concentrations. Concurrently, MH84 decreased protein levels of APP, Aβ1-42, and C-terminal fragments at micro-molar concentrations. Both Dimebon and DAPT reduced cellular Aβ1-42 levels. Dimebon improved mitochondrial functions and DAPT decreased mitochondrial membrane potential. Pioglitazone had no effects on APP processing and mitochondrial function. Our data emphasizes MH84 as possible novel therapeutic agent with mitochondria-based mode of action. | ||
|keywords=Alzheimer’s disease, Drug candidate, Mitochondrial dysfunction, Multifunctional agents, PGC1α, PPARγ-agonists, γ-Secretase modulators | |keywords=Alzheimer’s disease, Drug candidate, Mitochondrial dysfunction, Multifunctional agents, PGC1α, PPARγ-agonists, γ-Secretase modulators, HEK 293 cells | ||
|mipnetlab=DE Giessen Eckert GP, DE Frankfurt Eckert GP | |mipnetlab=DE Giessen Eckert GP, DE Frankfurt Eckert GP | ||
}} | }} | ||
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|tissues=Kidney, HEK | |tissues=Kidney, HEK | ||
|preparations=Permeabilized cells | |preparations=Permeabilized cells | ||
|couplingstates=LEAK, OXPHOS, | |couplingstates=LEAK, OXPHOS, ET | ||
|pathways=N, S, CIV, NS, ROX | |pathways=N, S, CIV, NS, ROX | ||
|instruments=Oxygraph-2k | |instruments=Oxygraph-2k | ||
|additional= | |additional=2016-11, | ||
}} | }} | ||
Latest revision as of 15:40, 13 November 2017
| Pohland M, Hagl S, Pellowska M, Wurglics M, Schubert-Zsilavecz M, Eckert GP (2016) MH84: a novel γ-secretase modulator/PPARγ agonist-improves mitochondrial dysfunction in a cellular model of Alzheimer's disease. Neurochem Res 41:231-42. |
Pohland M, Hagl S, Pellowska M, Wurglics M, Schubert-Zsilavecz M, Eckert GP (2016) Neurochem Res
Abstract: Developing new therapeutic strategies for Alzheimer's disease (AD) is a current challenge. Approved drugs merely act symptomatically and delay the progression of the disease for a relatively short period of time. Here, we investigated the effectiveness of MH84 in a cellular HEK293APPwt model of AD, characterized by elevated beta amyloid protein levels (Aβ1-42) and mitochondrial dysfunction. MH84 is a derivate of pirinixic acid belonging to a novel class of γ-secretase modulators, which combines γ-secretase modulation with activation of peroxisome proliferator-activator receptor gamma (PPARγ). The mitochondria modifying Dimebon, the γ-secretase blocker DAPT, and the PPARγ agonist pioglitazone were used as controls. MH84 protects against nitrosative stress, increased mitochondrial respiration, citrate synthase (CS) activity and protein levels of PGC1α indicating enhanced mitochondrial content at nano-molar concentrations. Concurrently, MH84 decreased protein levels of APP, Aβ1-42, and C-terminal fragments at micro-molar concentrations. Both Dimebon and DAPT reduced cellular Aβ1-42 levels. Dimebon improved mitochondrial functions and DAPT decreased mitochondrial membrane potential. Pioglitazone had no effects on APP processing and mitochondrial function. Our data emphasizes MH84 as possible novel therapeutic agent with mitochondria-based mode of action. • Keywords: Alzheimer’s disease, Drug candidate, Mitochondrial dysfunction, Multifunctional agents, PGC1α, PPARγ-agonists, γ-Secretase modulators, HEK 293 cells
• O2k-Network Lab: DE Giessen Eckert GP, DE Frankfurt Eckert GP
Labels: MiParea: Respiration, Pharmacology;toxicology
Pathology: Alzheimer's
Organism: Human Tissue;cell: Kidney, HEK Preparation: Permeabilized cells
Coupling state: LEAK, OXPHOS, ET
Pathway: N, S, CIV, NS, ROX
HRR: Oxygraph-2k
2016-11
