In a well-publicized article in the February 23, 2005 issue of the Journal of Neuroscience, researchers from Spain describe changes in cannabinoid receptors in the brains of AD patients, as well as animal behavioral and in-vitro data suggesting that cannabinoid agonists can protect neurons by reducing microglial activation.
The headlines on this study were predictably tantalizing (see, for example, "Marijuana May Block Alzheimer's"), but also misleading. The mass media stories barely dug beyond the paper’s stated implication that marijuana’s active ingredients could stem the progression of neurodegeneration. In reality, however, the story is more complicated and still unfolding. To begin with, two cannabinoid receptors have been identified. CB1 is the major type in brain, expressed by all types of nervous system cells, and apparently responsible for the psychoactive effects of the drug. CB2 is mainly expressed in immune system cells, but also in microglia (Benito et al., 2003), and may mediate neuroprotective effects of the drug. To complicate matters, cannabinoids may interact with other, still uncharacterized receptors.
There are many reports, in vivo as well as in vitro, of cannabinoids protecting neurons in models of excitotoxicity, ischemia, or trauma (see ARF related news story). This protection might result from effects on glutamate transmission or calcium flux. However, Pat McGeer and his colleagues at the University of British Columbia, Vancouver, have reported that agonists with affinity for both receptors are neurotoxic, a characteristic apparently mediated by CB1, whereas CB2-selective agonists can prevent microglia-mediated cell toxicity (Kegeris et al., 2003). Moreover, a group led by Julian Romero of the Fundacion Hospital Alcorcon in Madrid has reported increased expression of CB2 in AD brain, specifically in plaque-associated microglia, with no evidence of changes in CB1 levels (Benito et al., 2003). These researchers also reported finding both receptors in amyloid plaques.
The current paper, by María de Ceballos and colleagues at the Cajal Institute and Complutense University in Madrid, expands on these findings. In contrast to the study from Romero's group, first author Belén Ramírez and colleagues report a reduction in CB1 in AD brain. Specifically, neurons in the vicinity of activated microglia and CB1-containing plaques did not express CB1 in four of six AD cases. The authors also report that four of six AD cases showed a CB2-signal in dystrophic neurites and in neurons with evidence of tangles. Both receptors showed increased nitration in AD brain relative to control.
In one set of experiments, Ramírez and colleagues studied the interactions of cannabinoids and acutely administered Aβ in rats. In behavioral assessments of spatial learning, a nonselective CB1/CB2 agonist protected rats against Aβ-induced deficits. This cannabinoid also prevented Aβ-induced microglial activation in vivo, and counteracted Aβ-induced reductions in the neuronal proteins calbindin and α-tubulin, the authors report. In another set of experiments, this time in vitro, cannabinoid agonists prevented Aβ-induced microglial activation, regardless of whether they were CB2-specific or not, the authors write. Both agonists are reported to have blocked neurotoxicity induced by these activated microglia.
The authors note that in their microglia-neuron cell culture experiments, a CB2 receptor agonist was just as effective in protecting neurons as one that targets both cannabinoid receptors. They suggest that pursuing specifically the CB2 receptor in therapeutic strategies, rather than mixed-activity agonists, might avoid the psychoactive effects mediated by the CB1 receptor.
In contrast to this, McGeer and colleagues did not find CB1/CB2 agonists to be protective, but rather the opposite (Kegeris et al., 2003). "CB1 receptor agonists like THC are toxic to neurons and it would be a mistake to leave an impression, however indirect, that there might be some benefit to cannabis in AD," McGeer told ARF. "CB2 receptor agonists are clearly antiinflammatory, but if they also stimulate CB1 receptors, as do the ingredients of cannabis, the benefit will be offset by toxicity to neurons."—Hakon Heimer