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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, an endocannabinoid, is one such messenger produced in the postsynapse that inhibits neurotransmitter release upon activat... Full description

Journal Title: Brain 2011, Vol. 134(4), pp.1041-1060
Main Author: Mulder, Jan
Other Authors: Zilberter, Misha , PasquarÉ, , Susana J , AlpÁ, R, AlÁ, N , Schulte, Gunnar , Ferreira, Samira G , , Falvi, Attila , MartÍ, N - Moreno, Ana M , Keimpema, Erik , Tanila, Heikki , Watanabe, Masahiko , Mackie, Ken , HortobÁ, Gyi, Tibor , De Ceballos, Maria L , Harkany, Tibor
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ID: ISSN: 0006-8950 ; E-ISSN: 1460-2156 ; DOI: 10.1093/brain/awr046
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recordid: oxford10.1093/brain/awr046
title: Molecular reorganization of endocannabinoid signalling in Alzheimer’s disease
format: Article
creator:
  • Mulder, Jan
  • Zilberter, Misha
  • PasquarÉ
  • , Susana J
  • AlpÁ
  • R, AlÁ
  • N
  • Schulte, Gunnar
  • Ferreira, Samira G
  • Falvi, Attila
  • MartÍ
  • N - Moreno, Ana M
  • Keimpema, Erik
  • Tanila, Heikki
  • Watanabe, Masahiko
  • Mackie, Ken
  • HortobÁ
  • Gyi, Tibor
  • De Ceballos, Maria L
  • Harkany, Tibor
subjects:
  • Glia
  • Human
  • Neurodegeneration
  • Retrograde Signalling
  • Synapse
ispartof: Brain, 2011, Vol. 134(4), pp.1041-1060
description: Retrograde messengers adjust the precise timing of neurotransmitter release from the presynapse, thus modulating synaptic efficacy and neuronal activity. 2-Arachidonoyl glycerol, an endocannabinoid, is one such messenger produced in the postsynapse that inhibits neurotransmitter release upon activating presynaptic CB 1 cannabinoid receptors. Cognitive decline in Alzheimer’s disease is due to synaptic failure in hippocampal neuronal networks. We hypothesized that errant retrograde 2-arachidonoyl glycerol signalling impairs synaptic neurotransmission in Alzheimer’s disease. Comparative protein profiling and quantitative morphometry showed that overall CB 1 cannabinoid receptor protein levels in the hippocampi of patients with Alzheimer’s disease remain unchanged relative to age-matched controls, and CB 1 cannabinoid receptor-positive presynapses engulf amyloid-β-containing senile plaques. Hippocampal protein concentrations for the sn -1-diacylglycerol lipase α and β isoforms, synthesizing 2-arachidonoyl glycerol, significantly increased in definite Alzheimer’s (Braak stage VI), with ectopic sn -1-diacylglycerol lipase β expression found in microglia accumulating near senile plaques and apposing CB 1 cannabinoid receptor-positive presynapses. We found that microglia, expressing two 2-arachidonoyl glycerol-degrading enzymes, serine hydrolase α/β-hydrolase domain-containing 6 and monoacylglycerol lipase, begin to surround senile plaques in probable Alzheimer’s disease (Braak stage III). However, Alzheimer’s pathology differentially impacts serine hydrolase α/β-hydrolase domain-containing 6 and monoacylglycerol lipase in hippocampal neurons: serine hydrolase α/β-hydrolase domain-containing 6 expression ceases in neurofibrillary tangle-bearing pyramidal cells. In contrast, pyramidal cells containing hyperphosphorylated tau retain monoacylglycerol lipase expression, although at levels significantly lower than in neurons lacking neurofibrillary pathology. Here, monoacylglycerol lipase accumulates in CB 1 cannabinoid receptor-positive presynapses. Subcellular fractionation revealed impaired monoacylglycerol lipase recruitment to biological membranes in post-mortem Alzheimer’s tissues, suggesting that disease progression slows the termination of 2-arachidonoyl glycerol signalling. We have experimentally confirmed that altered 2-arachidonoyl glycerol signalling could contri
language:
source:
identifier: ISSN: 0006-8950 ; E-ISSN: 1460-2156 ; DOI: 10.1093/brain/awr046
fulltext: fulltext
issn:
  • 0006-8950
  • 00068950
  • 1460-2156
  • 14602156
url: Link


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