Therapeutic assessment of a novel mitochondrial complex I inhibitor in in vitro and in vivo models of Alzheimer's disease.

Background: Despite recent approval of monoclonal antibodies that reduce amyloid (Aβ) accumulation, the development of disease-modifying strategies targeting the underlying mechanisms of Alzheimer's disease (AD) is urgently needed.

Methods: We demonstrate that mitochondrial complex I (mtCI) represents a druggable target, where its weak inhibition activates neuroprotective signalling, benefiting AD mouse models with Aβ and p-Tau pathologies. Rational design and structure‒activity relationship studies yielded mtCI inhibitors profiled in a drug discovery funnel designed to address safety, selectivity, and efficacy.

Findings: The lead compound C458 is highly protective against Aβ toxicity, has favourable pharmacokinetics, and minimal off-target effects. C458 exhibited excellent brain penetrance, activating neuroprotective pathways with a single dose. Preclinical studies in APP/PS1 mice were conducted using functional tests, metabolic assessment, in vivo³¹P-NMR spectroscopy, blood cytokine panels, ex vivo electrophysiology, and Western blotting. Chronic oral administration improved long-term potentiation, reduced oxidative stress and inflammation, and enhanced mitochondrial biogenesis, antioxidant signalling, and cellular energetics. Efficacy against Aβ and p-Tau was confirmed in human organoids.

Interpretation: These studies provide further evidence that the restoration of mitochondrial function in response to mild energetic stress represents a promising disease-modifying strategy for AD.

Funding: This research was supported by grants from NIH AG 5549-06, NS1 07265, AG 062135, UG3/UH3 NS 113776, and ADDF 291204 (all to ET); U19 AG069701 (to TK); the Alzheimer's Association Research Fellowship grant 23AARF-1027342 (to TKON).