Partial Mitochondrial Complex I Inhibitors as a Therapy for Alzheimer Disease

Topic: Amyloid, tau and blood-test diagnosis

Like CP2, C458 and C273 weakly inhibit mtCI, leading to AMPK activation, which triggers a neuroprotective stress response. This response enhances oxidative stress protection, promotes autophagy, and increases mitochondrial biogenesis and turnover, ultimately protecting against Aβ toxicity. Pretreatment with the irreversible mtCI inhibitor rotenone (at non-toxic concentrations) blocked C458 and C273 from binding to mtCI and abrogated their protection against Aβ toxicity. Both C458 and C273 exhibited excellent bioavailability, blood-brain barrier penetrance, and a clean safety profile in the CEREP 44 safety panel. Chronic administration of C458 (25 mg/kg/day in drinking water ad lib) to APP/PS1 mice for 7 months preserved cognition, improved long-term potentiation, reduced oxidative stress and inflammation, and enhanced mitochondrial biogenesis. Similarly, C273 (20, 50, or 80 mg/kg/day) administered to C57BL/6 mice for one month showed no detectable side effects or toxicity in the heart or liver. Mechanistic studies revealed that C458 and C273 activate a mitochondrial stress response, augmenting mitochondrial biogenesis, antioxidant signaling, and autophagy, which collectively provided protection against Aβ toxicity in multiple in vitro and in vivo models of AD. These findings demonstrate that weak mtCI inhibition by novel compounds C458 and C273, with improved drug-like properties, is neuroprotective. This supports the feasibility of developing safe and efficacious mtCI inhibitors as a disease-modifying strategy for AD.

Key findings

• Like CP2, C458 and C273 weakly inhibit mtCI, leading to AMPK activation, which triggers a neuroprotective stress response.
• This response enhances oxidative stress protection, promotes autophagy, and increases mitochondrial biogenesis and turnover, ultimately protecting against Aβ toxicity.
• Pretreatment with the irreversible mtCI inhibitor rotenone (at non-toxic concentrations) blocked C458 and C273 from binding to mtCI and abrogated their protection against Aβ toxicity.
• Both C458 and C273 exhibited excellent bioavailability, blood-brain barrier penetrance, and a clean safety profile in the CEREP 44 safety panel.
• Chronic administration of C458 (25 mg/kg/day in drinking water ad lib) to APP/PS1 mice for 7 months preserved cognition, improved long-term potentiation, reduced oxidative stress and inflammation, and enhanced mitochondrial biogenesis.

Why it matters

In laboratory and mouse studies, the compounds C458 and C273 weakly inhibited mitochondrial complex I, triggering a neuroprotective stress response that protected against Aβ toxicity, and chronic C458 preserved cognition in APP/PS1 mice. These findings are from in vitro and animal models, so it is not yet known whether the compounds would work or be safe in people.

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Study details

• Evidence strengthLow

Read the original

• DOI: 10.1002/alz70859_105252
• PubMed: 41450141
• Original source →
• Free full text: Alzheimer s & Dementia →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

@article{trushin2025-41450141,
  author  = {Trushin, Sergey A. and Ostroot, Mark A. and Trushina, Eugenia V.},
  title   = {{Partial Mitochondrial Complex I Inhibitors as a Therapy for Alzheimer Disease}},
  journal = {Alzheimer s \& Dementia},
  year    = {2025},
  doi     = {10.1002/alz70859_105252},
  pmid    = {41450141},
  url     = {https://doi.org/10.1002/alz70859_105252}
}

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