Function of the endocannabinoid system in normal and pathological ageing processes of the brain
Final Report Abstract
Determination of key factors influencing the ageing process is crucial to understand and treat age-related diseases. Our project focused on the potential role of endocannabinoid system on brain ageing. We showed that young mice lacking cannabinoid receptor CB1 have a superior learning ability, which deteriorates rapidly in ageing. These age-related cognitive deficits were accompanied by early onset of neuronal loss and reduced neurogenesis, but not with significant histological changes in peripheral organs. We concluded that lack of CB1 receptor signaling leads to an early onset of brain ageing. In the ageing brain glia cells become activated and they release pro-inflammatory cytokines, which impairs neuronal activities and thus contributes to brain ageing. The age-related increase in the astrocyte and microglia activity was enhanced in old CB1 knockout mice. Unexpectedly, genetic deletion of CB1 receptors from GABAergic neurons led to a similar increase in neuroinflammation as observed in the constitutive CB1 knockouts. This result showed that 1. The cannabinoid system plays an important role in neuron-glia communication and 2. GABAergic cells have an important role in the regulation of microglial activity. A typical sign of cellular ageing is the intracellular accumulation of lipofuscin, an insoluble, fluorescent complex of non-degradable oxidized macromolecules. The increase in the lipofuscin content of hippocampal neurons had an earlier onset and was more intensive in CB1 knockout mice than in their wild-type littermates. The reason is this phenomenon was a lysosomal deficit in the knockout line due to a reduced expression of the lysosomal enzyme cathepsin D. The autophagy flow was upregulated in the CB1 knockout animals, but it could not compensate the negative effects of the lysosomal deficit and thus the accumulation of lipofuscin. Thus, endocannabinoid system influences besides neurogenesis and neuron-glia communication also the removal of degraded macromolecules. We learned from our study that reduced endocannabinoid system activity promotes ageing: it was important to know how cannabinoid system changes during ageing. In our publications we showed that the level of the major endogenous cannabinoid 2-arachidonoylglycerol and the coupling of CB1 receptors with the G-proteins decreases in ageing, thus the endocannabinoid system activity significantly declines during ageing. This change can contribute to the ageing of the brain, therefore we hypothesized that restoration of CB1 signaling could be a possible strategy to improve cognitive functions in the old. In our presently accepted paper we now show that a chronic low dose of Δ9-THC indeed restores cognitive functions in old mice. The long-lasting cognitive improvements in THC-treated old mice were associated with a significant change in hippocampal expression profiles that lasted for several weeks after cessation of the treatment. The direction of the expression changes were such that the profiles of old-THC mice were most similar to young control mice. Among the most striking expression changes was besides the activation of BDNF also a striking increase in the expression of Klotho, a gene known to exert a significant impact on the aging. This improvement in cognitive abilities, “rejuvenation” of gene expression profile was associated by enhanced synapse densities reaching similar values as observed in young control animals. Detailed histological analysis of the hippocampus showed that the number of dendritic spines and the density of Vglut1-positive excitatory terminals increased, whereas the density of Vgat-positive inhibitory terminals decreased in THC- treated old animals.
Publications
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Role of CB1 cannabinoid receptors on GABAergic neurons in brain aging. PNAS 2011, 108(27):11256-61
O.Albayram, J. Alferink, J. Pitsch, A. Piyanova, K. Neitzert, K. Poppensieker, D. Mauer, K. Michel, A. Legler, A. Becker, K. Monory, B. Lutz, A. Zimmer, A. Bilkei-Gorzo
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Early onset of aging-like changes is restricted to cognitive abilities and skin structure in Cnr1(-/-) mice. Neurobiol Aging. 2012, 33(1):200e11-22
Bilkei-Gorzo A, Drews E, Albayram O, Piyanova A, Gaffal E, Tueting T, Michel K, Mauer D, Maier W, Zimmer A
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Loss of CB1 receptors leads to differential age-related changes in reward-driven learning and memory. Front Aging Neurosci. 2012;4:34
Albayram O, Bilkei-Gorzo A, Zimmer A
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The endocannabinoid system in normal and pathological brain ageing. Phil.Trans.B. 2012, 367(1607):3326-42
Bilkei-Gorzo A
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Loss of CB1 receptors leads to decreased cathepsin D levels and accelerated lipofuscin accumulation in the hippocampus. Mech Ageing Dev. 2013 Sep;134(9):391-9
Piyanova A, Albayram O, Rossi CA, Farwanah H, Michel K, Nicotera P, Sandhoff K, Bilkei-Gorzo A
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Acute administration of THC impairs spatial but not associative memory function in zebrafish. Psychopharmacology (Berl). 2014 Oct;231(19):3829-42
Ruhl T, Prinz N, Oellers N, Seidel NI, Jonas A, Albayram O, Bilkei-Gorzo A, von der Emde G
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Age-related changes in the endocannabinoid system in the mouse hippocampus. Mech Ageing Dev. 2015 Sep;150:55-64
Piyanova A, Lomazzo E, Bindila L, Lerner R, Albayram O, Ruhl T, Lutz B, Zimmer A, Bilkei-Gorzo A
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Enhanced microglial activity in FAAH(-/-) animals. Life Sci. 2015 Oct 1;138:52-6
Ativie F, Albayram O, Bach K, Pradier B, Zimmer A, Bilkei-Gorzo A
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(2016) Lack of hippocampal CB1 receptor desensitization by Δ9-tetrahydrocannabinol in aged mice and by low doses of JZL 184. Naunyn-Schmiedeberg´s Arch Pharmacol, 2016 March 17; 389 (6): 603-12
Feliszek M, Bindila L, Lutz B, Zimmer A, Bilkei-Gorzo A, Schlicker E
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Physiological impact of CB1 receptor expression by hippocampal GABAergic interneurons. Pflugers Arch. 2016 Apr;468(4):727-37
Albayram Ö, Passlick S, Bilkei-Gorzo A, Zimmer A, Steinhäuser C
