Neuroprotective effects of cannabinoid ligands in a model of early Alzheimer pathogenesis
Creators: name: Boesch, Emily
Publisher: name: The University of North Carolina at Chapel Hill University Libraries
Year: 2020

description: Introduction: Alzheimer’s disease (AD) is a devastating neurodegenerative disorder, and there are currently no disease-modifying therapies available. Inflammation and network dysfunction precede the development of Alzheimer pathology and are thought to contribute to the development of pathology. Early intervention at this preliminary stage has the potential to modify the course of the disease. Cannabidiol (CBD) has both anti-inflammatory and network stabilizing effects which may be mediated through cannabinoid-like receptors such as GPR55. Our objective was to determine if CBD has neuroprotective properties in an in vitro model of Alzheimer’s disease pathogenesis and to identify the receptors through which CBD mediates its effects. Methods: To better understand the potential neuroprotective properties of CBD in early AD pathology, we evaluated calcium signaling and regulation of intracellular calcium in CBD-treated neurons challenged with an inflammatory stimulus. We also investigated the role of CBD as an anti-inflammatory agent by pretreating microglia with CBD before exposure to Aβo and then measuring the effects of the conditioned medium on neurons. We measured network stabilizing properties using microelectrode arrays to record the activity of neurons treated with CBD and challenged with an inflammatory stimulus. To investigate which receptors mediate the effects of CBD, we treated neurons and macrophages with cannabinoid ligands and measured the effect on calcium signaling. Results: CBD treatment of neurons offered partial protection against Aβ-induced inflammatory damage while CBD treatment of microglia conferred greater protection. In neurons, CBD increased and synchronized neuronal calcium signaling and network activity. The agonist stimulation profiles suggested that the neuroprotective effects of CBD may be induced by modulating GPR55 receptors. CBD induced an increased number of shorter electrophysiological bursts in neuronal network activity on the MEA indicating control over bursting activity that may contribute to protection. Network analysis of the effects of CBD indicated that it stabilized the neurons by suppressing hyperactivity.  When microglia were treated with CBD, the release of toxins from microglia was inhibited, indicating that an “anti-inflammatory” effect may confer neuroprotection than could exceed the effects on neurons.  Cannabinoid ligands each induced unique calcium signaling profiles on macrophages with CBD and NAGly inducing similar effects on calcium spike frequency suggesting modulation of the GPR18 receptor on macrophages. In addition, LPI induced strong and persistent activation of the macrophages, whereas 2-AG suppressed signaling indicating complex cannabinoid control of these cells.  Conclusions: Our findings support the hypothesis that CBD has neuroprotective potential for AD patients through the suppression of inflammation and regulation of network activity.  The mechanisms of CBD action are not well understood, but the findings indicate that actions at GPR55, GPR18, and other receptors are candidates for novel therapies that suppress pathogenesis in the early stages of Alzheimer’s disease.