Multi-modulators of PPARγ, γ-secretase, and mitochondrial function

Currently approved drugs for the treatment of Alzheimer`s disease (AD) act merely symptomatic and the progression of the disease is delayed for a relative short time period and most if not all new therapeutic approaches have failed in human clinical trials or already in preclinical development.

In the past years research much efforts were being made to identify new disease-modulating agents. In frame of the current project a novel class of dual PPARγ- (peroxisome proliferator-activated receptor γ) and γ-secretase modulators (GSM) to improve mitochondrial dysfunction in AD are developed. After synthesis the compounds are tested in human HEK293-APP695 cells and in mouse models of AD. Chemical modifications should increase the pharmacological potency of the synthesized GSM. Developed GSM so far don`t affect the physiological role of the γ-secretase especially in the Notch signaling pathway, but shift the processing of APP towards Aβ1-38(-40) which is less toxic compared to Aβ1-42. GSM also activate PPARγ. This nuclear receptor represents an important regulator of the lipid and glucose homeostasis, which is impaired in AD. Moreover, GSM improve mitochondrial function e.g. improve mitochondrial membrane potential and ATP levels. 

This project is supported by the Doktor Robert Pfleger-Stiftung and is carried out by Ph. D. student Maximilian Pohland in cooperation with Dr. Mario Wurglics and Prof. Manfred Schubert-Zsilavecz, Goethe-University of Frankfurt.

References

Pohland M, Hagl S, Pellowska M, Wurglics M, Schubert-Zsilavecz M, Eckert GP
MH84 - A novel γ-secretase modulator/PPARγ agonist - improves mitochondrial dysfunction in a cellular model of Alzheimer's disease
Neurochem Res, 2016, 41(1-2):231-42. [Pubmed Abstract]

Pellowska M, Stein C, Pohland M, Merk D, Klein J, Eckert GP, Schubert-Zsilavecz M, Wurglics M. Pharmacokinetic properties of MH84, a γ-secretase modulator with PPARγ agonistic activity
J Pharm Biomed Anal. 2014, 102C:417-424. [Pubmed Abstract]


© Prof. Dr. Gunter P. Eckert 2018