title: MH84: A Novel γ-Secretase Modulator/PPARγ Agonist--Improves Mitochondrial Dysfunction in a Cellular Model of Alzheimer's Disease.
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.
authors.affiliation: Institute of Pharmacology, Goethe University Frankfurt am Main, Max-von-Laue Str. 9, Frankfurt am Main, 60438, Germany.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Pohland
authors.affiliation: Institute of Pharmacology, Goethe University Frankfurt am Main, Max-von-Laue Str. 9, Frankfurt am Main, 60438, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Hagl
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe University Frankfurt am Main, Max-von-Laue Str. 9, Frankfurt am Main, 60438, Germany.
authors.forename: Maren
authors.initials: M
authors.lastname: Pellowska
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe University Frankfurt am Main, Max-von-Laue Str. 9, Frankfurt am Main, 60438, Germany.
authors.forename: Mario
authors.initials: M
authors.lastname: Wurglics
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe University Frankfurt am Main, Max-von-Laue Str. 9, Frankfurt am Main, 60438, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Schubert-Zsilavecz
authors.affiliation: Institute of Pharmacology, Goethe University Frankfurt am Main, Max-von-Laue Str. 9, Frankfurt am Main, 60438, Germany. g.p.eckert@em.uni-frankfurt.de.
authors.forename: Gunter P
authors.initials: GP
authors.lastname: Eckert
mesh_terms: D000544:Alzheimer Disease / Q000503:physiopathology*; D053829:Amyloid Precursor Protein Secretases / Q000187:drug effects*; D057809:HEK293 Cells; D006801:Humans; D008928:Mitochondria / Q000502:physiology*; D008954:Models, Biological; D047495:PPAR gamma / Q000819:agonists*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology*; D014157:Transcription Factors / Q000502:physiology
chemical_list: D047495:PPAR gamma; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011743:Pyrimidines; D014157:Transcription Factors; C006253:pirinixic acid; D053829:Amyloid Precursor Protein Secretases
keywords: Alzheimer’s disease; Drug candidate; Mitochondrial dysfunction; Multifunctional agents; PGC1α; PPARγ-agonists; γ-Secretase modulators