MH84: A Novel γ-Secretase Modulator/PPARγ Agonist—Improves Mitochondrial Dysfunction in a Cellular Model of Alzheimer's Disease
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- 作者：Maximilian Pohland ; Stephanie Hagl ; Maren Pellowska…
- 关键词：Alzheimer’s disease ; Mitochondrial dysfunction ; γ ; Secretase modulators ; PPARγ ; agonists ; PGC1α ; Multifunctional agents ; Drug candidate
- 刊名：Neurochemical Research
- 出版年：2016
- 出版时间：February 2016
- 年：2016
- 卷：41
- 期：1-2
- 页码：231-242
- 全文大小：1,763 KB
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Stephanie Hagl (1)
Maren Pellowska (2)
Mario Wurglics (2)
Manfred Schubert-Zsilavecz (2)
Gunter P. Eckert (1)
1. Institute of Pharmacology, Goethe University Frankfurt am Main, Max-von-Laue Str. 9, Frankfurt am Main, 60438, Germany
2. Institute of Pharmaceutical Chemistry, Goethe University Frankfurt am Main, Max-von-Laue Str. 9, Frankfurt am Main, 60438, Germany - 刊物类别：Biomedical and Life Sciences
- 刊物主题：Biomedicine
Neurosciences
Biochemistry
Neurology - 出版者：Springer Netherlands
- ISSN：1573-6903
文摘
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.