This article examines the evidence involving the endocannabinoid system  with regard to the symptomatology or treatment of the neurodegenerative disease. On the basis of this evidence, we present the probable efficacy of endocannabinoid-based therapies to treat Alzheimer’s disease.

Several studies have mapped the localization of cannabinoid receptors in tissues and at a subcellular level, and these have been instrumental in our understanding of the effects of cannabinoids on Alzheimer’s disease. CB1 receptors are expressed in the central and peripheral nervous system, while at the subcellular level it has been located to presynaptic terminals.

Initially, early studies suggested that CB2 was not present in the brain. However, several studies have now shown the expression of CB2 in sick brain cells in Alzheimer’s disease. These studies and others provide strong evidence that the CB2 receptor is regulated in response to inflammatory signals or activation of immune cells.

Several synthetic and degrading enzymes have been identified that dynamically regulate the levels of endogenous cannabinoids, under normal and diseased conditions, and which may be key targets for therapy.

The endocannabinoids in neurodegenerative diseases

Thanks to the increasing understanding of the functions of endogenous cannabinoids, it has been suggested that there are two main pathways in which cannabinoids can affect neurodegenerative processes: Neuromodulation and immunomodulation.

Several revisions have well identified the neuromodulatory action of endocannabinoids and the transduction of the CB1 and CB2 signals. In fact, it has been shown that endocannabinoids synthesized by depolarized post-synaptic nerve cells can act as a retrograde substance with CB1, located in presynaptic terminals. This would inhibit the release of excitatory neurotransmitters or inhibitors of the pre-synaptic neuron.

Apart from this crucial regulatory role in neuron activity, CB2 is expressed in different circulating and resident immune cells. Particularly when these cells are activated, and their agonism is typically associated with a dampening of their pro-inflammatory activities. This includes inhibiting the release of inflammatory mediators, inhibiting the activation of cell-mediated immune processes, and inhibiting proliferation and chemotaxis.

In fact, there is preliminary scientific evidence that cannabis provides symptomatic relief in various neurodegenerative disorders. These include multiple sclerosis, Huntington’s disease, Parkinson’s and Alzheimer’s disease,  and amyotrophic lateral sclerosis.

Interaction of cannabinoids with Alzheimer’s disease

The disruptive effects of Δ9-THC in memory are well documented and have recently been more fully characterized at the molecular level. Therefore, Alzheimer’s disease has been investigated for evidence on the dysfunction of the endocannabinoid system resulting from, or contributes to, the pathophysiology of the disease.

Neurodegeneration appears to follow the extracellular deposition of the β-amyloid protein in “plaques” and/or the formation of intracellular “ravels” of hyperphosphorylated tau protein. The finding that CB2 is expressed in microglia grouped around β-amyloid plaques, suggests that endocannabinoids may have the ability to modulate the effector cells of Alzheimer’s disease.

On the other hand, it has been shown that synthetic Δ9-THC (dronabinol) alleviates behavioral disorders, weight loss, symptoms of nocturnal agitation, in human studies of Alzheimer’s and severe dementia respectively. Pharmacologic dissection suggests that these endocannabinoids can mediate neuroprotection through activation of CB1, inhibiting inflammatory microglial response through activation of CB2.

In a study conducted by Esposito, the CB2 antagonist was able to attenuate the markers of astrogliosis. The unifying hypothesis that covers most of these studies is that the pathological changes in the levels of endocannabinoids and the expression of CB2 are induced by the inflammatory environment that occurs in Alzheimer’s disease.

The activation of CB2 by endocannabinoids is regulated to the point of stopping microglial activation, however, is insufficient in preventing subsequent inflammatory damage to neurons, which may also suffer a loss of protection due to the Regulation to the low of CB1. Based on the preclinical efficacy already demonstrated, cannabinoid stimulators can have a therapeutic benefit by increasing the innate response of the brain.

A general paradigm in the diseases summarized in this article is that the hiccup function or deregulation of the endocannabinoid system can be responsible for part of the symptoms of these diseases. In Huntington’s disease, Alzheimer’s disease, as well as in ALS, pathological changes in endocannabinoid levels and the expression of CB2 are induced by the inflammatory environment.

The studies described in this review are an integral part of Alzheimer’s disease or a symptom of it, highlighting the potential role that endocannabinoids can play in both the protection of cells of the disease process and in the Treatment of symptoms. CB1 activation has been shown to be effective in limiting cell death after lesions by extoxication and to cushion the inflammatory response of cells immune to Alzheimer’s disease. These two objectives can therefore work together to provide neuroprotection to acute injury and immune suppression during more chronic responses.

References:

[1] Benito C, Nunez E, Tolon RM, Carrier EJ, Rabano A, Hillard CJ et al. (2003). Cannabinoid CB2  receptors and fatty acid amide hydrolase are selectively overexpressed in neuritic plaque-associated glia in Alzheimer’s disease brain. J Neurosct 23: 11136-11141

[2] Ehrhart J, Obregon D, Mori T, Hou H, Sun N, Bai Y et al. (2005). Stimulation of cannabinoid receptor 2 (CB2) suppresses microglial activationJ Neuroinflammation 2: 29.

[3] Esposito G, Iuvone T, Savani C, Scuderi C, De Filippis D, Papa M et al. (2007). Opposing control of cannabinoid receptor stimulation on amyloid-beta-induced reactive gliosis: in vitro and in vivo evidence. J Pharmacol Exp Ther 322: 1144-1152

[4] Felder C, Joyce K, Briley E, Mansouri J, Mackie K, Blond O et al. (1995). Comparison of the pharmacology and signal transduction of the human cannabinoid CB1 and CB2 receptorsMol Pharmacol 48: 443-450

[5] Ferri CP, Prince M, Brayne C, Brodaty H, Fratiglioni L, Ganguli M et al. (2005). Global prevalence of dementia: a Delphi consensus studyLancet 366: 2112-2117

[6] Minati L, Edginton T, Bruzzone MG, Giaccone G (2009). Current concepts in Alzheimer’s disease: a multidisciplinary review. Am J Alzheimers Dis Other Demen 24: 95-121

[7] Puighermanal E, Marsicano G, Busquets-Gracia A, Lutz B, Maldonado R, Ozaita A (2009). Cannabinoid modulation of hippocampal long-term memory is mediated by mTOR signalingNat Neurosci 12: 1152-1158

[8] Ramirez BG, Blazquez C, Gomez del Pulgar T, Guzman M, de Ceballor ML (2005). Prevention of Alzheimer’s disease pathology by cannabinoids: neuroprotection mediated by blockade of microglial activation. J Neurosci 25: 1904-1913

[9] Walther S, Mahlberg R, Eichmann U, Kunz D (2006). Delta-9-tetrahydrocannabinol for nighttime agitation in severe dementia. Psychopharmacology (Berl) 185: 524-528

[10] Wilson RI, Nicoll RA (2001). Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses.Nature 410: 588-592