Cannabinoid advances up close: Alzheimer’s Disease
Alzheimer’s disease is a progressive neurodegenerative disorder, typically of old age, associated most often with cognitive impairment and memory decline. At the neurological level it presents as fibrillary tangles and extracellular amyloid-β-peptide lesions, or ‘plaques’, and enlarged axonal endings.
The body’s endocannabinoid system, part of our onboard neural signaling network (and the reason we are sensitive to administered cannabinoids), has anti-inflammatory, antioxidant, and neurogenic capabilities of potential benefit to Alzheimer’s patients. Modulation of this system by pharmacological cannabinoids is therefore emerging as a promising therapeutic goal.
Research has shown, for example, that the activation of both cannabinoid receptors (‘CB1’ and ‘CB2’), by natural or synthetic agonists, at non-psychoactive doses, reduces harmful amyloid-β peptide action, tau phosphorylation, and neurofibrillary tangles, and enhances the brain’s intrinsic repair mechanism as wells. Endocannabinoid signaling has also been demonstrated to modulate concomitant pathological processes, including neuroinflammation, excitotoxicity, mitochondrial dysfunction, and oxidative stress. In population-based studies, cannabinoids reduce dementia-related behavioral disturbances.
Evidence implicating the endocannabinoid system
That cannabinoid receptors are important in the pathology of Alzheimer’s disease is beyond doubt. Senile plaques in Alzheimer’s patients express cannabinoid receptors CB1 and CB2, together with markers of microglial activation. CB1-positive neurons, present in high numbers in control cases, are also greatly reduced in areas of microglial activation. In pharmacological experiments, G-protein coupling and CB1 receptor protein expression are markedly decreased in Alzheimer’s brains. Additionally, protein nitration is increased, at both receptor sites. Intracerebroventricular administration of the synthetic cannabinoid WIN55,212-2 in animal models prevents amyloid-β-induced microglial activation, cognitive impairment, and loss of neuronal markers. WIN55,212-2 and the experimental synthetics HU-210 JWH-133 block amyloid-β-induced activation of cultured microglial cells, on the evidence of mitochondrial activity, cell morphology, and tumor necrosis factor-alpha release. JWH-133 has also attenuated okadaic acid-induced spatial memory impairment and neurodegeneration in rats. Moreover, cannabinoids ameliorate microglia-mediated neurotoxicity after amyloid-β addition to animal cortical cocultures. Finally, results from a 2018 study show sensitivity of activated microglial cells to cannabinoids, and increased CB1-CB2 Het expression in activated microglia. Moreover, amyloid-β infusion in animals does associate with gliosis and memory impairment, and these effects can then be reversed by CB1, CB2 or mixed activation.
Much research has focussed on the two receptor sites individually.
Post-mortem analysis of Alzheimer’s brains finds increases in the expression of CB1, often in cortical areas, though CB1 levels do not correlate with Alzheimer markers or cognitive status. Genetic deletion of CB1 has been shown to exacerbate the Alzheimer-like symptoms in one transgenic animal model. Likewise, in another animal study, CB1 blockade enables inflammation.
Upregulation of CB2 receptors is a common pattern of response to chronic injury of the human central nervous system. It is at CB2 that receptor deficiency increases amyloid pathology and alters tau processing in transgenic mice. CB2 receptor activation also improves cognitive impairment of hippocampal Sox2 in animal models. In Alzheimer’s brains, CB2 increase has been clearly identified on microglia, where it does correlate with amyloid-β level and the presence of plaques. Conversely, CB2 deficiency results in reduced neuroinflammation. Stimulation of CB2, moreover, suppresses microglial activation. It is not clear whether CB2 modulation benefits arise from reduction of neuroinflammatory processes or by the reduction of amyloid-β activation of the neuroinflammatory system. There is some evidence that though CB2 functions in amyloid-β in Alzheimer's disease, it may actually play only a minor role in future therapeutic intervention.
Much remains to be understood about the mechanisms of action relative to CB2. It has been found, for example, by in-vivo brain imaging and kinetic modeling of the CB2 tracer [11C]NE40 in Alzheimer’s patients and healthy controls, that there is actually lower CB2 binding in Alzheimer’s disease, and no relationship between amyloid load and CB2 availability. It may be that [11C]NE40 binds to CB2 with lower affinity or selectivity than to CB1. Another observation is that up-regulation of fatty acid amide hydrolase (FAAH) occurs within plaques, and might be responsible for an increase in metabolites, such as arachidonic acid, from degradation of anandamide, an endocannabinoid, and in this way contribute to the inflammatory process. Mice lacking FAAH, which is mediated by both CB receptors, do show diminished soluble amyloid levels, plaques, and gliosis. It should be noted that pharmacologic inhibition of FAAH in 5xFAD mice has little impact on the expression of key enzymes and cytokines, or on cognitive impairment, plaque deposition, or gliosis. But genetic inactivation of FAAH in 5xFAD mice does lead to increased expression of inflammatory cytokines , who exhibit improvement in spatial memory.
There is a special glucoregulatory role for CB2 that may have ramifications on the neuropathology of Alzheimer’s disease. In mice, both selective (JWH133 and GP1a) and non-selective (WIN55212-2) CB2R agonists, but not the CB1R-selective agonist, ACEA, stimulate glucose uptake, in a manner that is sensitive to the CB2R-selective antagonist, AM630. Glucose uptake is stimulated in astrocytes and neurons in culture, in acute hippocampal slices, in different brain areas of young adult male C57Bl/6j and CD-1 mice, as well as in middle-aged C57Bl/6j mice. Among the endocannabinoid metabolizing enzymes, the selective inhibition of COX-2, rather than that of FAAH, MAGL or α,βDH6/12, also stimulates the uptake of glucose in hippocampal slices of middle-aged mice, an effect that was again prevented by AM630. However, the levels of the endocannabinoid anandamide decline in the hippocampus of TgAPP-2576 mice (a model of β-amyloidosis), and likely because of this, COX-2 inhibition fails to stimulate glucose uptake in these mice.
Toward a therapeutic strategy
From all this, it is clear that administered cannabinoids should offer a multi-faceted approach for the treatment of Alzheimer's disease, through neuroprotection, reduction of neuroinflammation, and support of the brain's own repair mechanisms, this latter principally by augmenting neurotrophin expression and enhancing neurogenesis.
A landmark 2018 study showed, for the first time, that the administration of an endocannabinoid can indeed prevent Alzheimer’s-like effects induced by streptozotocin in rats.
Other trials have shown effects of cannabinoid compounds on vessel density in amyloid precursor protein (APP) transgenic mice, and altered vascular responses in aorta isolated rings. First was shown increased collagen IV positive vessels in Alzheimer’s brains compared to control subjects, with a similar increase in TgAPP mice, which was normalized by prolonged oral treatment with WIN 55,212-2 and the CB2 selective agonist JWH-133. In Tg APP mice vasoconstriction induced by phenylephrine and the thromboxane agonist U46619 was significantly increased, and there was no change in vasodilation to acetylcholine. Tg APP showed decreased vasodilation with both cannabinoid agonists, which were able to prevent the expected decreased ACh relaxation in the presence of amyloid-β. Thus is confirmed the existence of altered vascular responses in Tg APP mice.
WIN, 2-AG,a synthetic cannabinoid, and methanandamide,the R-(+)-analog of a series of methylated congeners of anandamide, a cannabinoid receptor agonist, have together fully prevented the hemichannel activity and inflammatory profile evoked by amyloid-β in astrocytes. Moreover, they have fully abolished the amyloid-β-induced release of excitotoxic glutamate and associated ATP to astrocyte Cx43 hemichannel activity, and as well neuronal damage in hippocampal slices exposed to amyloid-β. This opens alternative treatments for consideration, that target astrocytes.
WIN-55,212-2shows potential value in chronic neuroinflammation in young and aged rats, and neurogenic and cognitive benefits in aged animals. This may be because of its activity on TRPV1 receptors and its activation of the PPAR-γ pathway and, in cultured astrocytes, its amplification of the expression of the antioxidant Cu/Zn.
Anandamide, one of the main phytocannabinoids, is involved in several physiological functions, notably neuroprotection. With treatment, FAAH activity decreases in the frontal cortex from human patients with Alzheimer's disease, and this effect is mimicked by the amyloid-β(1-40) peptide. In rats, this increases in cerebrocortical membranes and decreases in synaptosomes. The concomitant presence of JWH-133, the CB2 selective agonist, slightly raises anandamide hydrolysis in human controls, and decreases this activity in adults and aged rat cerebrocortical membranes and synaptosomes. The same is true in the presence of WIN55,212-2.
Cannabidiol (CBD) possesses neuroprotective, antioxidant and anti-inflammatory properties and reduces amyloid-β production and tau hyperphosphorylation in vitro, and has also been shown to be effective in vivo, where long-term treatment prevents the development of social recognition memory deficits in Alzheimer's disease transgenic mice. Likewise it reverses deficits in hippocampal long-term potentiation. Studies overall demonstrate the ability of CBD to reduce reactive gliosis and neuroinflammatory response and promote neurogenesis in in-vivo Alzheimer models.
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The foregoing is a report on trends and developments in the cannabinoid industry. No product described herein is intended to diagnose, treat, cure or prevent any disease or syndrome.