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Cited by 33Alzheimer's disease research and treatmentsMitochondrial Function and PathologyCholinesterase and Neurodegenerative Diseases

MH84 improves mitochondrial dysfunction in a mouse model of early Alzheimer’s disease

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Pohland, Maximilian, Pellowska, Maren, Asseburg, Heike, Hagl, Stephanie, Reutzel, Martina, Joppe, Aljoscha, Berressem, Dirk, Eckert, Schamim H. +3 more·2018·Alzheimer's Research & Therapy
DOI 10.1186/s13195-018-0342-6PMC PMC5809956
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Abstract

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 AβPP SL 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. Three-month-old Thy-1 AβPP SL 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 Aβ 1–40 and Aβ 1–42 levels were determined using ELISA. Western blot analysis and qRT-PCR were used to measure protein and mRNA levels, respectively. 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. 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.

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  • Brain mitochondria in AD patients have dysfunctional respiratory chain complexes and decreased ATP generation.

    “Brain mitochondria in AD patients have shown dysfunctional respiratory chain complexes and decreased ATP generation”

    From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [59]

    The Results section (‘MH84 reversed mitochondrial dysfunction’; page unavailable) reports decreased complex IV respiration in brain mitochondria and decreased ATP levels in dissociated brain cells from an AD mouse model. The Background discusses respiratory-enzyme defects in AD generally, but the paper does not establish these specific findings in brain mitochondria from AD patients. (LLM, conf=0.88)

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Authors
Pohland, M., Pellowska, M., Asseburg, H., Hagl, S., Reutzel, M., Joppe, A., Berressem, D., Eckert, S. H., Wurglics, M., Schubert‐Zsilavecz, M., & Eckert, G. P.
Affiliations
  • Goethe University Frankfurt (DE)
  • Justus-Liebig-Universität Gießen (DE)
Corresponding author
Eckert, Gunter P.
ORCID
Venue
Alzheimer's Research & Therapy
Publisher
Springer Science and Business Media LLC
Published
2018-02-13
Volume
10
Issue
1
Pages
18-18
ISSN
1758-9193 (ISSN-L)
DOI
10.1186/s13195-018-0342-6
PMC
PMC5809956
OpenAlex
W2807658485
Cited by
33
References
6
Citations by year
2026: 1 · 2025: 7 · 2024: 3 · 2023: 5 · 2022: 2 · 2021: 2 · 2020: 8 · 2019: 4 · 2018: 1
FWCI
2.49
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Alzheimer s Research & Therapy (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • University writing server of the Justus Liebig University Giessen (Justus-Liebig-Universität Gießen) (submittedVersion, cc-by)
  • Publication Server of Goethe University Frankfurt am Main (Goethe University Frankfurt) (submittedVersion, cc-by)
Funders
  • Robert Pfleger Foundation
  • Heinrich Sauer and Josef Schmidt Foundation
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
Keywords
Alzheimer's disease, mitochondrial dysfunction, PPARγ, gamma-secretase, amyloid precursor protein, APP processing, beta-secretase, C99, amyloid-beta, PGC-1α, cytochrome c oxidase, mitochondrial respiration, mitochondrial membrane potential, ATP, oral bioavailability, brain mitochondria
MeSH terms
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Adenosine Triphosphate, Alzheimer Disease, Animals, Brain, Caproates, Electron Transport Complex IV, Disease Models, Animal, Humans, Mice, Inbred C57BL, Mice, Transgenic, Mitochondria, Peptide Fragments, Pyrimidines, RNA, Messenger, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Neuroprotective Agents, Brain-Derived Neurotrophic Factor, Mitochondrial Diseases, Membrane Potential, Mitochondrial, HEK293 Cells

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