Pohland 2016 Neurochem Res

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Pohland M, Hagl S, Pellowska M, Wurglics M, Schubert-Zsilavecz M, Eckert GP (2016) MH84: a novel Ξ³-secretase modulator/PPARΞ³ agonist-improves mitochondrial dysfunction in a cellular model of Alzheimer's disease. Neurochem Res 41:231-42.

Β» PMID: 26721513

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 (AΞ²1-42) and mitochondrial dysfunction. MH84 is a derivate of pirinixic acid belonging to a novel class of Ξ³-secretase modulators, which combines Ξ³-secretase modulation with activation of peroxisome proliferator-activator receptor gamma (PPARΞ³). The mitochondria modifying Dimebon, the Ξ³-secretase blocker DAPT, and the PPARΞ³ agonist pioglitazone were used as controls. MH84 protects against nitrosative stress, increased mitochondrial respiration, citrate synthase (CS) activity and protein levels of PGC1Ξ± indicating enhanced mitochondrial content at nano-molar concentrations. Concurrently, MH84 decreased protein levels of APP, AΞ²1-42, and C-terminal fragments at micro-molar concentrations. Both Dimebon and DAPT reduced cellular AΞ²1-42 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. β€’ Keywords: Alzheimer’s disease, Drug candidate, Mitochondrial dysfunction, Multifunctional agents, PGC1Ξ±, PPARΞ³-agonists, Ξ³-Secretase modulators, HEK 293 cells

β€’ 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 


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