Mitochondria are the power plants of the cell, packaging chemical energy store molecules through the activities of electron transport chain protein complexes. Some forms of interference in the operation of these complexes can be beneficial, causing mild stress that provokes the cell into greater maintenance activities. This usually results in better cell function, greater cell resilience, and so forth, leading to better organ function and a slowing of the aging process. Researchers here demonstrate that this sort of approach is beneficial in a mouse model of Alzheimer's disease, reducing the damage done to neurons. It is, nonetheless, a compensatory approach, not a form of repair that addresses underlying issues. The utility is necessarily limited, as those underlying issues remain in place, still causing all the other downstream harms they are capable of.
Recent studies demonstrated that altered energy homeostasis associated with reduced cerebral glucose uptake and utilization, altered mitochondrial function and microglia and astrocyte activation might underlie neuronal dysfunction in Alzheimer's disease (AD). Intriguingly, accumulating evidence suggests that non-pharmacological approaches, such as diet and exercise, reduce major AD hallmarks by engaging an adaptive stress response that leads to improved metabolic state, reduced oxidative stress and inflammation, and improved proteostasis. While mechanisms of the stress response are complex, AMP-activated protein kinase (AMPK)-mediated signaling has been directly linked to the regulation of cell metabolism, mitochondrial dynamics and function, inflammation, oxidative stress, protein turnover, Tau phosphorylation, and amyloidogenesis. However, the development of direct pharmacological AMPK activators to elicit beneficial effects has presented multiple challenges.
We recently demonstrated that mild inhibition of mitochondrial complex I (MCI) with the small molecule tricyclic pyrone compound CP2 blocked cognitive decline in transgenic mouse models of AD when treatment was started in utero through life or at a pre-symptomatic stage of the disease. Moreover, in neurons, CP2 restored mitochondrial dynamics and function and cellular energetics. However, it was unclear whether MCI inhibition would elicit similar benefits if administered at the advanced stage of the disease, after the development of prominent Aβ accumulation, brain hypometabolism, cognitive dysfunction, and progressive neurodegeneration. As a proof of concept, we demonstrate that partial inhibition of MCI triggers stress-induced AMPK-dependent signaling cascade leading to neuroprotection and a reversal of behavior changes in symptomatic APP/PS1 female mice, a translational model of AD. Beneficial effect of treatment could be monitored using translational biomarkers currently utilized in clinical trials.