MH84: A Novel gamma-Secretase Modulator/PPAR gamma Agonist-Improves Mitochondrial Dysfunction in a Cellular Model of Alzheimer's Disease

摘要

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 (A beta(1-42)) and mitochondrial dysfunction. MH84 is a derivate of pirinixic acid belonging to a novel class of gamma-secretase modulators, which combines gamma-secretase modulation with activation of peroxisome proliferator-activator receptor gamma (PPAR gamma). The mitochondria modifying Dimebon, the gamma-secretase blocker DAPT, and the PPAR gamma agonist pioglitazone were used as controls. MH84 protects against nitrosative stress, increased mitochondrial respiration, citrate synthase (CS) activity and protein levels of PGC1 alpha indicating enhanced mitochondrial content at nano-molar concentrations. Concurrently, MH84 decreased protein levels of APP, A beta(1-42), and C-terminal fragments at micro-molar concentrations. Both Dimebon and DAPT reduced cellular A beta(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.