Neuroinflammation and Aging
Neuroinflammation refers to the activation of immune cells in the central nervous system (CNS) in response to a wide variety of stimuli, including infectious diseases, autoimmune or neurodegenerative disorders, peripheral nerve damage, or stress. Albeit the CNS has long been regarded as an immunologically privileged site because of the presence of the blood brain barrier (BBB), there is now ample evidence that CNS immune functions are mediated by activated resident microglial cells and infiltrating immune cells. This neuroinflammatory response may exert protective, but also detrimental effects and is suggested to be a “double-edged sword”. Our research focuses on the potential dual role of antigen presenting cells, with particular emphasis on microglial and immigrating dendritic cells (DCs). We investigate this question by using gene-targeted, conditional knockout or bone marrow (BM)-chimeric mice in mouse models for chronic pain, Alzheimer`s disease, multiple sclerosis or infectious encephalitis.
Of special interest is the role of the endocannabinoid system as a modulator of neuroinflammatory responses. Almost everyone knows cannabinoids (the bioactive compounds of the hemp plant Cannabis sativa), because cannabis in form of marihuana and hashish is still the most widely consumed illegal drug.
Starting point for the scientific research of the effects of cannabinoids on brain functions was the discovery, of its major psychoactive component Δ9-tetrahydrocannabinol (THC) more than 35 year ago (Gaoni and Mechoulam, 1971). THC activates two G-protein coupled receptors, the cannabinoid receptors type 1 and 2 (CB1 and CB2). The endogenous ligands (endocannabinoids) of these receptors are the lipid signaling molecules acylethanolamines (NAEs) and monoacylglycerols (MAGs), which are synthesized from membrane phospholipids. The primary MAG, 2-arachidonoylglycerol (2-AG) (Kogan and Mechoulam, 2006; Pertwee, 2005), is generated through hydrolysis of the diacylglycerol by sn-1 selective DAG lipases DAGLα and DAGLß (Bisogno et al, 2003). The major NAE is arachidonoylethanolamide (anandamide, AEA). Its biosynthesis is rather complex involving multiple parallel pathways. The regulation of the biosynthetic pathways is not well understood, but Ca2+ dependent and independent processes have been implicated (Di Marzo, 2009). The degradation of AEA is mediated by the fatty acid amide hydrolase (FAAH), while the most important catabolic enzymes for 2-AG are the monoacylglycerol lipases (MAGLs) and to a lesser extend alpha-beta-hydrolase 6 and 12 (Abhd6 and 12) (Dinh et al, 2002; Fiskerstrand et al, 2010; Marrs et al, 2010).
The CB1 receptor is predominantly expressed throughout the brain and mediates virtually all of the central nervous system effects of THC. In contrast, CB2 receptors mainly found on non-neuronal cells, such as in immune and bone cells (Atwood and Mackie, 2010). Both receptors signal via the Gi/o subclass of G-proteins (Bab and Zimmer, 2008; Elphick and Egertova, 2001; Rodriguez de Fonseca et al, 2005).
In the central nervous system, endocannabinoids are synthesized in the postsynaptic compartment in a regulated manner. They diffuse through the synaptic cleft and activate pre-synaptic CB1 receptors, which results in an inhibition of neurotransmitter release. This endocannabinoid-mediated retrograde feedback mechanism is the molecular basis of important short- and long-term changes in synaptic signaling.
Our laboratory has generated mouse strains with deletions in both cannabinoid receptors. These animal models have been instrumental in the elucidation of ECS functions. Thus, mice lacking CB1 receptors show a number of behavioral changes and they are resistant for most of the central nervous system effects of cannabinoids. Importantly, many drugs of abuse are less rewarding in the absence of CB1 signaling, thus revealing the involvement of the ECS in drug addiction. CB1 receptor deficient mice also show an increased mortality and a rapid age-dependent decline in cognitive and memory performance. Mice without CB2 receptors show striking changes in immune and inflammatory responses. In general, immune responses seem to be enhanced in the absence of CB2 signaling, which suggest a role for the ECS in the negative control of the immune system. We have recently demonstrated that the lack of this inhibitory mechanism leads to a spread of spinal cord neuroinflammation associated with peripheral nerve injury. This in turn resulted in an increase in pain sensitivity that was also present in tissues that were not directly affected by the nerve damage.
The endocannabinoid system is at the focus of many research projects within the Institute.
Atwood BK, Mackie K (2010). CB2: a cannabinoid receptor with an identity crisis. British journal of pharmacology 160(3): 467-479.
Bab I, Zimmer A (2008). Cannabinoid receptors and the regulation of bone mass. British journal of pharmacology 153(2): 182-188.
Bisogno T, Howell F, Williams G, Minassi A, Cascio MG, Ligresti A, et al (2003). Cloning of the first sn1-DAG lipases points to the spatial and temporal regulation of endocannabinoid signaling in the brain. The Journal of cell biology 163(3): 463-468.
Di Marzo V (2009). The endocannabinoid system: its general strategy of action, tools for its pharmacological manipulation and potential therapeutic exploitation. Pharmacol Res 60(2): 77-84.
Dinh TP, Carpenter D, Leslie FM, Freund TF, Katona I, Sensi SL, et al (2002). Brain monoglyceride lipase participating in endocannabinoid inactivation. Proceedings of the National Academy of Sciences of the United States of America 99(16): 10819-10824.
Elphick MR, Egertova M (2001). The neurobiology and evolution of cannabinoid signalling. Philos Trans R Soc Lond B Biol Sci 356(1407): 381-408.
Fiskerstrand T, H'Mida-Ben Brahim D, Johansson S, M'Zahem A, Haukanes BI, Drouot N, et al (2010). Mutations in ABHD12 cause the neurodegenerative disease PHARC: An inborn error of endocannabinoid metabolism. Am J Hum Genet 87(3): 410-417.
Gaoni Y, Mechoulam R (1971). The isolation and structure of delta-1-tetrahydrocannabinol and other neutral cannabinoids from hashish. J Am Chem Soc 93(1): 217-224.
Kogan NM, Mechoulam R (2006). The chemistry of endocannabinoids. Journal of endocrinological investigation 29(3 Suppl): 3-14.
Marrs WR, Blankman JL, Horne EA, Thomazeau A, Lin YH, Coy J, et al (2010). The serine hydrolase ABHD6 controls the accumulation and efficacy of 2-AG at cannabinoid receptors. Nature neuroscience 13(8): 951-957.
Pertwee RG (2005). Pharmacological actions of cannabinoids. Handbook of experimental pharmacology(168): 1-51.
Rodriguez de Fonseca F, Del Arco I, Bermudez-Silva FJ, Bilbao A, Cippitelli A, Navarro M (2005). The endocannabinoid system: physiology and pharmacology. Alcohol Alcohol 40(1): 2-14.