Article series: The endocannabinoid system

Endocannabinoid signalling and the deteriorating brain

Journal name:
Nature Reviews Neuroscience
Year published:
Published online


Ageing is characterized by the progressive impairment of physiological functions and increased risk of developing debilitating disorders, including chronic inflammation and neurodegenerative diseases. These disorders have common molecular mechanisms that can be targeted therapeutically. In the wake of the approval of the first cannabinoid-based drug for the symptomatic treatment of multiple sclerosis, we examine how endocannabinoid (eCB) signalling controls — and is affected by — normal ageing and neuroinflammatory and neurodegenerative disorders. We propose a conceptual framework linking eCB signalling to the control of the cellular and molecular hallmarks of these processes, and categorize the key components of endocannabinoid signalling that may serve as targets for novel therapeutics.

At a glance


  1. Main biosynthetic and inactivating enzymes in endocannabinoid signalling.
    Figure 1: Main biosynthetic and inactivating enzymes in endocannabinoid signalling.

    The subcellular distribution in neurons of enzymes regulating the levels of endocannabinoids (eCBs) is shown, including the proposed role of these lipid mediators in retrograde (mainly for 2-arachidonoyl-glycerol (2-AG)), anterograde and intracellular (for anandamide (AEA)) signalling. The biosynthesis of AEA occurs through the action, among others, of N-acylphosphatidylethanolamine (NAPE)-specific phospholipase D (NAPE-PLD), which is located in intracellular membranes both pre- and postsynaptically. AEA is degraded by fatty acid amide hydrolase 1 (FAAH), which is located postsynaptically. This distribution of the enzymes responsible for synthesis and degradation of AEA enables this and other N-acylethanolamines (NAEs) to function as anterograde signals acting at postsynaptic targets, or as intracellular mediators. 2-AG is biosynthesized by diacylglycerol lipase-α (DAGLα), which is located postsynaptically, and degraded by monoacylglycerol lipase (MAGL), which instead is presynaptic, thus accounting for the retrograde signalling action suggested for this endocannabinoid (see Fig. 2b). The complexity arising from the fact that many of these enzymes also regulate the levels of eCB-related mediators, with non-cannabinoid receptors as targets, is also depicted. For further complexity in eCB signalling see Fig. 4 and Supplementary Information S1 (table). Solid arrows denote transformation into active metabolites or activation; dashed arrows denote transformation into metabolites inactive at cannabinoid receptors; blunt arrow denotes inhibition. AA, arachidonic acid; AGs, 2-acylglycerols; DAGs, diacylglycerols; ER, endoplasmic reticulum; GPRs, orphan G-protein-coupled receptors; MAPK, mitogen-activated protein kinases; PIP2, phosphoinositide bisphosphate; PKA, protein kinase A; PLCβ, phospholipase Cβ; PPARs, peroxisome proliferator-activated receptors; TRPs, transient receptor potential channels; VGCCs, voltage-gated calcium channels.

  2. Age-related changes at different system levels and their regulation by endocannabinoid signalling. Ageing is accompanied by changes in cellular processes, impairments in the integration of cellular activities, and deficits in physiological functions.
    Figure 2: Age-related changes at different system levels and their regulation by endocannabinoid signalling. Ageing is accompanied by changes in cellular processes, impairments in the integration of cellular activities, and deficits in physiological functions.

    a | At the cellular level, important hallmarks of ageing in the CNS are impairments in mitochondrial functions, disruption of proteostasis and autophagy, and alterations in signalling pathways involved in nutrient sensing, such as the mammalian target of rapamycin (mTOR) pathway. Endocannabinoids (eCBs) act as intracellular signalling molecules that modulate mitochondrial activity through cannabinoid type 1 (CB1) receptors located either in the plasma membrane or on lysosomes (l-CB1) and possibly mitochondria (m-CB1). In particular, activation of m-CB1 seems to reduce mitochondrial respiration, and to decrease mitochondrial cyclic AMP levels and protein kinase A (PKA) activity111. CB1 receptors located on lysosomes enhance the intracellular release of Ca2+, increase the permeability of lysosomes and the release of cathepsin D. CB1 receptors on the cell surface also stimulate mTOR signalling, through an Akt-dependent mechanism, resulting in an enhanced activity of phosphoprotein 70 ribosomal protein S6 kinase (p70S6K). The mechanism by which cannabinoids stimulate autophagy is not entirely clear (indicated by a question mark), and is probably independent of mTOR. b | At the tissue level, disruption of intercellular communication is another hallmark of ageing. Endocannabinoids are best known as signalling molecules for short-range cell–cell communication. At synapses they provide a retrograde feedback system, in which activation of presynaptic CB1 receptors reduces neurotransmitter release probability. Endocannabinoids also modulate the activity of astrocytes and microglia. These cells may also be a source for brain endocannabinoids (eCBs). Increased numbers of activated microglia and astrocytes are typically found in the ageing brain and result in an increased production of pro-inflammatory cytokines (PICs). This process leads to a change towards a more pro-inflammatory milieu in the brain. c | At the organism level, eCBs modulate the activity of several systems that are important in ageing, such as metabolic processes or hypothalamic activity. Cannabinoids are generally protective against age-related pathologies, including neuroinflammation and neurodegeneration. They also protect against some age-related pathologies outside the CNS, such as osteoporosis58. Akt, serine/threonine Akt; DAG, diacylglycerol; DAGLs, diacylglycerol lipases; DSI, depolarization-induced suppression of inhibitory neurotransmission; Glu, Glutamate; IC, intracellular; mGluR, metabotropic glutamate receptor; NMDA, N-methyl-d-aspartate; PKA, protein kinase A; TRP, transient receptor potential channel.

  3. Effect of neuroinflammation on endocannabinoid signalling.
    Figure 3: Effect of neuroinflammation on endocannabinoid signalling.

    a | In healthy brain tissue, neurons express cannabinoid receptor 1 (CB1) receptors in the dendritic tree and also higher levels at axon terminals. Resting microglia express low levels of CB2 receptors73. Endocannabinoid (eCB) production by neurons is high (indicated by the thick arrows), whereas eCB production in microglia is low (indicated by the thinner arrow). b | In diseased brain in which the immune system has been activated (for example, in multiple sclerosis), the cell-specific expression profile of cannabinoid receptors changes, resulting in lower levels of CB1 receptors in both the dendritic tree and axon terminal of neurons and higher expression of CB2 receptors in activated microglia. In addition, T cells expressing low levels of CB2 receptors invade the diseased brain area75, 77. eCB production by neurons decreases (indicated by the thinner arrows), while eCB production in microglia increases (thick arrow). This overall change in the cell-specific expression profile of cannabinoid receptors and eCB levels in brain as a function of disease and possibly of the ageing process suggests that the responses of humans to cannabinoid-based therapeutics is likely to differ depending on the age of the patient and disease phase.

  4. The endocannabinoidome in neurodegenerative diseases.
    Figure 4: The endocannabinoidome in neurodegenerative diseases.

    The complexity of the alterations of components of the endocannabinoid (eCB) system and of some elements of the 'endocannabinoidome', in terms of redundancy of metabolic pathways, involvement of non-cannabinoid type 1 (CB1), non-CB2 receptors and tissue- or time-dependent changes is summarized. Time-dependent changes of the brain levels of some of the eCB synthesizing and inactivating enzymes and eCBs, and of the expression of eCB molecular targets, in animal models of neurodegenerative diseases (and, when available, in post-mortem brains of patients with these disorders) are depicted with their potential consequences. Red lines indicate changes in 2-arachidonoyl-glycerol (2-AG) and its metabolic enzymes or products over time during the progression of either Huntington's or Alzheimer's disease. Time-dependent changes in anandamide (AEA) and fatty acid amide hydrolase 1 (FAAH) over the course of these diseases are shown in blue. Purple lines denote changes in CB1 and CB2 during Alzheimer's and Huntington's disease. Note that CB1 and CB2 receptor levels are unchanged in Alzheimer's disease and Huntington's disease, respectively (not shown). Dashed branches show when a mediator begins to be partially metabolized into another one. In this case, the levels of the mediator being transformed start being reduced and those of its product start being increased. Note how the levels of AEA and 2-AG may change in different or opposite ways in the two conditions. They can also produce opposite effects147, 148, depending on the production of cyclooxygenase 2 (COX2) metabolites (in the case of 2-AG)125, 126, 127, 128 or because of activation of non-cannabinoid receptors (for example, transient receptor potential cation channel subfamily V member 1 (TRPV1) channels in the case of AEA)116, 117. Also within the same disorder, a given eCB may first increase and then decrease (as with 2-AG in Alzheimer's disease)147, or change in opposite ways in different brain areas or blood (as with AEA in Huntington's disease)149. Finally, some of the features of Alzheimer's disease, such as the formation of 2-AG-derived prostaglandins, or the participation of CB1 receptors in determining some of the symptoms148, also occur in models of Parkinson's disease. DSI, depolarization-induced suppression of inhibitory neurotransmission; MSNs, medium-spiny neurons; PGE2-GE, prostaglandin E2 glycerol ester.


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Author information


  1. Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Via Campi Flegrei 34, 80078 Pozzuoli, Naples, Italy.

    • Vincenzo Di Marzo
  2. Department of Pharmacology, University of Washington.

    • Nephi Stella
  3. Department of Psychiatry and Behavioral Science, University of Washington, 1959 Pacific Avenue North, Seattle, Washington 98103, USA.

    • Nephi Stella
  4. Institute for Molecular Psychiatry, University of Bonn, Sigmund Freud Straße 25, Bonn 53127, Germany.

    • Andreas Zimmer

Competing interests statement

VD acts as a consultant for GW Pharmaceuticals, UK, VD receives unrestricted grants from GW Pharmaceuticals, UK, and Allergan, USA

Corresponding author

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  • Vincenzo Di Marzo

    Vincenzo Di Marzo is Director of the Institute of Biomolecular Chemistry of the Consiglio Nazionale delle Ricerche in Naples, Italy, and the coordinator of its Endocannabinoid Research Group. He received his Masters degree in Chemistry from the University of Naples 'Federico II', Naples, Italy, and his Ph.D. in Biochemistry from Imperial College, London, UK. He has worked on endocannabinoids since 1992 and his later research has included a focus on the pharmacology of plant cannabinoids. Vincenzo Di Marzo's homepage

  • Nephi Stella

    Nephi Stella is a professor of pharmacology, psychiatry and behavioural sciences at the University of Washington in Seattle, USA. He studied biology at the University of Geneva, Switzerland, and received his Ph.D. in physiology from the University of Lausanne, Switzerland. He carried out his postdoctoral training on endocannabinoid production at the Neurosciences Institute in San Diego, USA, and has been at the University of Washington since 1999, where he worked first on endocannabinoid signalling and neuroinflammation, neurodegeneration, and more recently on neuro-oncology.

  • Andreas Zimmer

    Andreas Zimmer is a professor and Director of the Institute of Molecular Psychiatry at the University of Bonn, Germany. His main interest is the role of endocannabinoid signalling in animal behaviour and psychiatric disorders. He studied biology at the University of Giessen, Germany, where he also received his Ph.D. He spent more than a decade at the National Institute of Mental Health, Bethesda, USA, where he worked on CNS development and later on the endocannabinoid system. Andreas Zimmer's homepage

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  1. Supplementary information S1 (table) (362 KB)

    The “endocannabinoidome”. Endocannabinoids, endocannabinoid-related mediators and their metabolic enzymes and receptors.

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