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MH84 improves mitochondrial dysfunction in a mouse model of early Alzheimer's disease
Maximilian Pohland1, Maren Pellowska2, Heike Asseburg1,3
1Institute of Pharmacology, Goethe University, Frankfurt, Germany.
Background:
Current approved drugs for Alzheimer's disease (AD) only attenuate symptoms, but do not cure the disease. The pirinixic acid derivate MH84 has been characterized as a dual gamma-secretase/proliferator activated receptor gamma (PPARγ) modulator in vitro. Pharmacokinetic studies in mice showed that MH84 is bioavailable after oral administration and reaches the brain. We recently demonstrated that MH84 improved mitochondrial dysfunction in a cellular model of AD. In the present study, we extended the pharmacological characterization of MH84 to 3-month-old Thy-1 AβPPSL mice (harboring the Swedish and London mutation in human amyloid precursor protein (APP)) which are characterized by enhanced AβPP processing and cerebral mitochondrial dysfunction, representing a mouse model of early AD.
Methods:
Three-month-old Thy-1 AβPPSL mice received 12 mg/kg b.w. MH84 by oral gavage once a day for 21 days. Mitochondrial respiration was analyzed in isolated brain mitochondria, and mitochondrial membrane potential and ATP levels were determined in dissociated brain cells. Citrate synthase (CS) activity was determined in brain tissues and MitoTracker Green fluorescence was measured in HEK293-AβPPwt and HEK293-AβPPsw cells. Soluble Aβ1-40 and Aβ1-42 levels were determined using ELISA. Western blot analysis and qRT-PCR were used to measure protein and mRNA levels, respectively.
Results:
MH84 reduced cerebral levels of the β-secretase-related C99 peptide and of Aβ40 levels. Mitochondrial dysfunction was ameliorated by restoring complex IV (cytochrome-c oxidase) respiration, mitochondrial membrane potential, and levels of ATP. Induction of PPARγ coactivator-1α (PGC-1α) mRNA and protein expression was identified as a possible mode of action that leads to increased mitochondrial mass as indicated by enhanced CS activity, OXPHOS levels, and MitoTracker Green fluorescence.
Conclusions:
MH84 modulates β-secretase processing of APP and improves mitochondrial dysfunction by a PGC-1α-dependent mechanism. Thus, MH84 seems to be a new promising therapeutic agent with approved in-vivo activity for the treatment of AD.
Insights
MH84, a novel drug candidate, effectively reduces amyloid-beta peptides and improves mitochondrial function in an Alzheimer
Area of Science:
- Neuroscience and Pharmacology
- Mitochondrial Biology
- Alzheimer's Disease Research
Background:
- Current Alzheimer's disease (AD) treatments only manage symptoms, not the underlying pathology.
- MH84, a pirinixic acid derivative, acts as a dual gamma-secretase/proliferator activated receptor gamma (PPARγ) modulator.
- MH84 demonstrates oral bioavailability, brain penetration, and has previously improved mitochondrial dysfunction in cellular AD models.
Purpose of the Study:
- To pharmacologically characterize MH84 in a mouse model of early Alzheimer's disease (Thy-1 AβPPSL mice).
- To evaluate MH84's effects on amyloid precursor protein (APP) processing and mitochondrial dysfunction in vivo.
- To elucidate the mechanism of action of MH84 in an AD mouse model.
Main Methods:
- Administration of MH84 (12 mg/kg) via oral gavage to 3-month-old Thy-1 AβPPSL mice for 21 days.
- Assessment of mitochondrial respiration, membrane potential, ATP levels, and citrate synthase activity in brain tissues.
- Quantification of soluble Aβ1-40 and Aβ1-42 using ELISA; analysis of protein and mRNA levels via Western blot and qRT-PCR.
Main Results:
- MH84 treatment significantly reduced cerebral levels of the C99 peptide and Aβ40.
- Mitochondrial function was restored, evidenced by improved complex IV respiration, membrane potential, and ATP levels.
- MH84 induced PPARγ coactivator-1α (PGC-1α) expression, increasing mitochondrial mass and oxidative phosphorylation (OXPHOS).
Conclusions:
- MH84 effectively modulates APP processing via the β-secretase pathway.
- MH84 ameliorates mitochondrial dysfunction through a PGC-1α-dependent mechanism.
- MH84 shows promise as a therapeutic agent for Alzheimer's disease with demonstrated in vivo efficacy.