Targeting mitochondria for healthy brain aging: a case study of non‐psychoactive cannabinoids to rescue mitochondrial dysfunction in Alzheimer’s disease

Abstract

AbstractBackgroundAlzheimer’s disease (AD) arises from complex and multifaceted pathogenic mechanisms. Although many alterations occur in the aging brain that are likely to contribute to AD, there is growing evidence that mitochondrial inefficiency and dysfunction are one of the pathophysiological changes contributing to neurodegeneration in AD. The oxytosis/ferroptosis regulated cell death pathway recapitulates many features of mitochondrial dysfunction associated with the aging brain and has emerged as a potential key mediator of neurodegeneration. It has thus been proposed that the oxytosis/ferroptosis pathway could be used to identify novel AD drug candidates that act by preserving mitochondrial function.MethodsAiming to identify AD drug candidates from natural products that preserve mitochondrial function, we have focused on phytochemical libraries with medicinal properties. We used a novel preclinical drug‐screening platform based on phenotypic assays that mimic different cellular toxicities and stresses associated with the AD brain that are characterized by mitochondrial dysfunction. To elucidate the molecular mechanisms for mitochondrial regulation, we harnessed an inducible, mitochondrially‐depleted neuronal cell line and employed the combined techniques of live‐cell imaging, super‐resolution microscopy, real‐time mitochondrial metabolic analysis, biochemical assays, immunoblotting, and qPCR.ResultsUsing this combined approach, we discovered that cannabinol (CBN), a non‐psychoactive cannabinoid, is a novel and potent neuroprotector. We demonstrated that not only does CBN protect neurons from oxytosis/ferroptosis in a manner that is dependent on mitochondria, it does so independently of cannabinoid CB1/CB2 receptors. Specifically, CBN alleviates intraneuronal amyloid toxicity, directly targets mitochondria, and preserves key mitochondrial functions including redox regulation, calcium uptake, membrane potential, bioenergetics, biogenesis, and modulation of fusion/fission dynamics that are disrupted following induction of oxytosis/ferroptosis in neuronal cells. These neuroprotective effects of CBN are at least partly mediated by the promotion of endogenous antioxidant defenses and the activation of AMP‐activated protein kinase (AMPK) signaling which help to maintain mitochondrial homeostasis.ConclusionsThis study highlights the potential of mitochondrially‐targeted compounds such as CBN as novel oxytotic/ferroptotic inhibitors to rescue mitochondrial dysfunction for healthy brain aging, as well as opportunities for the discovery and development of future therapeutics for Alzheimer’s disease and other age‐associated neurological disorders.