Molecular reorganization of endocannabinoid signalling in Alzheimer's disease.

Retrograde messengers adjust the precise timing of neurotransmitter release from the presynapse, thus modulating synaptic efficacy and neuronal activity. 2-Arachidonoyl glycerol (2-AG), an endocannabinoid, is one such messenger produced in the postsynapse that inhibits neurotransmitter release upon activating presynaptic CB1 cannabinoid receptors (CB1Rs). Cognitive impairment in Alzheimer¿s disease (AD) is due to synaptic failure in hippocampal neuronal networks. We hypothesized that errant retrograde 2-AG signalling impairs synaptic neurotransmission in AD. Comparative protein profiling and quantitative morphometry showed that overall CB1R protein levels in the hippocampi of AD patients remain unchanged relative to age-matched controls, and CB1R+ presynapses engulf ¿-amyloid (A¿)-containing senile plaques. Hippocampal protein concentrations for sn-1-diacylglycerol lipases ¿ and ß (DAGL¿/¿), synthesizing 2-AG, significantly increase in definite AD (Braak stage VI), with ectopic DAGL¿ expression found in microglia accumulating near senile plaques and apposing CB1R+ presynapses. We find that microglia expressing two 2-AG-degrading enzymes, serine hydrolase ¿/¿-hydrolase domain-containing 6 (ABHD6) and monoacylglycerol lipase (MGL), begin to surround senile plaques in probable AD (Braak stage III). However, AD pathology differentially impacts ABHD6 and MGL in hippocampal neurons: ABHD6 expression ceases in neurofibrillary tangle-bearing pyramidal cells. In contrast, pyramidal cells containing hyperphosphorylated tau retain MGL expression, although at levels significantly lower than in neurons lacking neurofibrillary pathology. Here, MGL accumulates in CB1R+ presynapses. Subcellular fractionation revealed impaired MGL recruitment to biological membranes in post-mortem AD tissues, suggesting AD-related modifications to terminating 2-AG signalling. We have experimentally confirmed that altered 2-AG signalling could contribute to synapse silencing in AD by demonstrating si