MH84: A Novel γ-Secretase Modulator/PPARγ Agonist—Improves Mitochondrial Dysfunction in a Cellular Model of Alzheimer’s Disease

• Published in: Neurochemical research Vol. 41; no. 1-2; pp. 231 - 242
• Main Authors: Pohland, Maximilian, Hagl, Stephanie, Pellowska, Maren, Wurglics, Mario, Schubert-Zsilavecz, Manfred, Eckert, Gunter P.
• Format: Journal Article
• Language: English
• Published: New York Springer US 01-02-2016
• Subjects: Alzheimer Disease - physiopathology; Amyloid Precursor Protein Secretases - drug effects; Biochemistry; Biomedical and Life Sciences; Biomedicine; Cell Biology; HEK293 Cells; Humans; Mitochondria - physiology; Models, Biological; Neurochemistry; Neurology; Neurosciences; Original Paper; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; PPAR gamma - agonists; Pyrimidines - chemistry; Pyrimidines - pharmacology; Transcription Factors - physiology; Multifunctional agents; Mitochondrial dysfunction; γ-Secretase modulators; Alzheimer’s disease; PGC1α; Drug candidate; PPARγ-agonists
• ISSN: 0364-3190; 1573-6903
• DOI: 10.1007/s11064-015-1765-0

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
APPwt
model of AD, characterized by elevated beta amyloid protein levels (Aβ
1–42
) 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, Aβ
1–42
, and C-terminal fragments at micro-molar concentrations. Both Dimebon and DAPT reduced cellular Aβ
1–42
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.