2-Arachidonoyl glycerol signalling in Alzheimer's disease

JAN MULDER; SUSANA PASQUARÉ; TIBOR HORTOBÁGYI; ANA M. MARTÍN-MORENO; KEN MACKIE; HEIKKI TANILA; MARÍA L. DE CEBALLOS; TIBOR HARKANY

Amsterdam, The Netherlands

Congreso; 7th FENS FORUM of European Neuroscience; 2010

Jan Mulder1, Susana Pasquaré2,3, Tibor Hortobágyi4, Ana M. Martín-Moreno2, Ken Mackie5, Heikki Tanila6, María L. de Ceballos2, Tibor Harkany1,7. Addresses 1ENI-Aberdeen, University of Aberdeen, Aberdeen, United Kingdom; 2Department of Cellular, Molecular and Developmental Neurobiology, Instituto Cajal, Madrid, Spain, 3Instituto de Investigaciones Bioquímicas de Bahía Blanca, Universidad Nacional del Sur and Consejo Nacional de Investigaciones Científicas y Técnicas, Bahía Blanca, Argentina, 4Institute of Psychiatry, King´s College London, London, United Kingdom; 5Gill Center and Department of Psychological and Brain Sciences, Indiana University, Bloomington, United States, 6University of Eastern Finland, Kuopio, Finland, 7Karolinska Institutet, Stockholm, Sweden Title 2-Arachidonoyl glycerol signaling in Alzheimer´s disease Text Retrograde endocannabinoid (eCB) signalling modulates the plasticity of many excitatory and inhibitory synapses in the cerebral cortex. The molecular architecture of 2-arachidonoyl glycerol (2-AG) signaling networks is suited to allow fast, ´on demand´2-AG release from subsynaptic dendrites of functionally active neurons with 2-AG subsequently engaging presynaptic CB1 cannabinoid receptors (CB1Rs) to suppress neurotransmitter release from presynaptic terminals. Diacylglyerol lipases (DGLs) and monoglyceride lipase (MGL), enzymes underpinning 2-AG synthesis and degradation, respectively, are primary determinants that set, sustain and terminate 2-AG bioavailability at cortical synapses. We hypothesize a molecular role of eCBs in the changes in synaptic plasticity underpinning Alzheimer´s disease (AD). Cortical Abeta accumulation in AD can render eCB signaling insufficient by impairing excitability-dependent DGL functions in corticolimbic neurons and, consequently, remove retrograde signaling as a means to maintain the temporal precision of neurotransmitter release.We have used human pathology, transgenic, and pharmacology tools to decipher molecular rearrangements in 2-AG signalling system in AD. We confirmed pre- and postsynaptic reorganization in functionally-impaired corticolimbic neuronal networks in both post-mortem human brain and transgenic models. We find that CB1R levels are largely static, but in contrast, DGLalpha/beta and MGL levels undergo substantial age-related decline that already in early and mid-stage AD surpass those seen in age-matched controls. Changes in DGL and MGL expression preferentially correlate with major sites of cytoskeletal rearrangments during AD progression emphasizing that the integrity of local pre- and postsynaptic microdomains setting the rate of 2-AG metabolism but not cross-modal changes at synapses is a primary determinant of 2-AG signaling. Transgenic models demonstrate that a metabolic insufficiency of 2-AG signaling underpins impaired glutamate and GABA neurotransmission in corticolimbic territories.These findings demonstrate that i) tangible changes in 2-AG turnover underscore impaired synaptic signaling in AD and ii) modulation of 2-AG bioavailability and signal transduction attenuate AD-related cognitive impairment. Theme C - Disorders of the nervous system Alzheimer´s disease and other dementias / Cellular