Mitochondrial Manipulation and the Quest for Alzheimer's Treatments

Alzheimer's disease (AD) implies the presence of progressive cognitive decline to the point an individual cannot manage their daily affairs (dementia), in conjunction with intraneuronal accumulations of tau protein (tangles) in defined cortical regions and extracellular cortical accumulations of beta amyloid protein (Aβ plaques). Our ability to define AD does not mean we fully understand it; AD definitions themselves continue to evolve and disagreements over its causes remain (Swerdlow, 2007). All agree, though, that better treatments are needed. It is this need the study of Zhang et al. (published in this issue of EBioMedicine) sought to address (Zhang et al., in press). Members of this group previously reported a tricyclic pyrone compound, CP2, ameliorated Aβ toxicity in a cell culture setting, reduced fibrillary and non-fibrillar Aβ species in an AD transgenic mouse model, and in fact directly bound Aβ (Zhang et al., in press). Observations reported in the current study by Zhang, Trushina, and colleagues, though, indicate that this compound's biological effects transcend its ability to directly bind Aβ. Through a series of elegant experiments, it was deduced that CP2 competitively occupies the flavin mononucleotide (FMN) redox site within complex I, a respiratory chain holoenzyme on themitochondrial innermembrane, thereby inhibiting its function. Unlike other complex I inhibitors, CP2-mediated complex I inhibition does not seem to induce oxidative stress or inflammation, perhaps by limiting the initial entry