INIBIBB   05455
INSTITUTO DE INVESTIGACIONES BIOQUIMICAS DE BAHIA BLANCA
Unidad Ejecutora - UE
artículos
Título:
Molecular reorganization of endocannabinoid signalling in Alzheimers disease
Autor/es:
JAN MULDER; MISHA ZILBERTER; PASQUARÉ S.J.; ALAN ALPAR; GUNNAR SCHULTE; SAMIRA G. FERREIRA; ATTILA KOFALVI; ANA M. MARTÍN-MORENO; ERIK KEIMPEMA; HEIKKI TANILA; MASAHIKO WATANABE; KEN MACKIE; TIBOR HORTOBAGYI; MARIA L. DE CEBALLOS; TIBOR HARKANY
Revista:
BRAIN
Editorial:
OXFORD UNIV PRESS
Referencias:
Año: 2011 p. 1041 - 1060
ISSN:
0006-8950
Resumen:
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 CB1 cannabinoid receptors. Cognitive decline in Alzheimers
disease is due to synaptic failure in hippocampal neuronal networks. We hypothesized that errant retrograde 2-arachidonoyl
glycerol signalling impairs synaptic neurotransmission in Alzheimers disease. Comparative protein profiling and quantitative
morphometry showed that overall CB1 cannabinoid receptor protein levels in the hippocampi of patients with Alzheimers
disease remain unchanged relative to age-matched controls, and CB1 cannabinoid receptor-positive presynapses engulf
amyloid-b-containing senile plaques. Hippocampal protein concentrations for the sn-1-diacylglycerol lipase a and b isoforms,
synthesizing 2-arachidonoyl glycerol, significantly increased in definite Alzheimers (Braak stage VI), with ectopic sn-
1-diacylglycerol lipase b expression found in microglia accumulating near senile plaques and apposing CB1 cannabinoid
receptor-positive presynapses. We found that microglia, expressing two 2-arachidonoyl glycerol-degrading enzymes, serine
hydrolase a/b-hydrolase domain-containing 6 and monoacylglycerol lipase, begin to surround senile plaques in probable
Alzheimers disease (Braak stage III). However, Alzheimers pathology differentially impacts serine hydrolase a/b-hydrolase
domain-containing 6 and monoacylglycerol lipase in hippocampal neurons: serine hydrolase a/b-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 CB1 cannabinoid receptor-positive presynapses. Subcellular fractionation
revealed impaired monoacylglycerol lipase recruitment to biological membranes in post-mortem Alzheimers tissues,
suggesting that disease progression slows the termination of 2-arachidonoyl glycerol signalling. We have experimentally confirmed
that altered 2-arachidonoyl glycerol signalling could contribute to synapse silencing in Alzheimers disease by demonstrating
significantly prolonged depolarization-induced suppression of inhibition when superfusing mouse hippocampi with
amyloid-b. We propose that the temporal dynamics and cellular specificity of molecular rearrangements impairing
2-arachidonoyl glycerol availability and actions may differ from those of anandamide. Thus, enhanced endocannabinoid signalling,
particularly around senile plaques, can exacerbate synaptic failure in Alzheimers disease.a/b-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 CB1 cannabinoid receptor-positive presynapses. Subcellular fractionation
revealed impaired monoacylglycerol lipase recruitment to biological membranes in post-mortem Alzheimers tissues,
suggesting that disease progression slows the termination of 2-arachidonoyl glycerol signalling. We have experimentally confirmed
that altered 2-arachidonoyl glycerol signalling could contribute to synapse silencing in Alzheimers disease by demonstrating
significantly prolonged depolarization-induced suppression of inhibition when superfusing mouse hippocampi with
amyloid-b. We propose that the temporal dynamics and cellular specificity of molecular rearrangements impairing
2-arachidonoyl glycerol availability and actions may differ from those of anandamide. Thus, enhanced endocannabinoid signalling,
particularly around senile plaques, can exacerbate synaptic failure in Alzheimers disease.1 cannabinoid receptor-positive presynapses. Subcellular fractionation
revealed impaired monoacylglycerol lipase recruitment to biological membranes in post-mortem Alzheimers tissues,
suggesting that disease progression slows the termination of 2-arachidonoyl glycerol signalling. We have experimentally confirmed
that altered 2-arachidonoyl glycerol signalling could contribute to synapse silencing in Alzheimers disease by demonstrating
significantly prolonged depolarization-induced suppression of inhibition when superfusing mouse hippocampi with
amyloid-b. We propose that the temporal dynamics and cellular specificity of molecular rearrangements impairing
2-arachidonoyl glycerol availability and actions may differ from those of anandamide. Thus, enhanced endocannabinoid signalling,
particularly around senile plaques, can exacerbate synaptic failure in Alzheimers disease.b. We propose that the temporal dynamics and cellular specificity of molecular rearrangements impairing
2-arachidonoyl glycerol availability and actions may differ from those of anandamide. Thus, enhanced endocannabinoid signalling,
particularly around senile plaques, can exacerbate synaptic failure in Alzheimers disease.1 cannabinoid receptors. Cognitive decline in Alzheimers
disease is due to synaptic failure in hippocampal neuronal networks. We hypothesized that errant retrograde 2-arachidonoyl
glycerol signalling impairs synaptic neurotransmission in Alzheimers disease. Comparative protein profiling and quantitative
morphometry showed that overall CB1 cannabinoid receptor protein levels in the hippocampi of patients with Alzheimers
disease remain unchanged relative to age-matched controls, and CB1 cannabinoid receptor-positive presynapses engulf
amyloid-b-containing senile plaques. Hippocampal protein concentrations for the sn-1-diacylglycerol lipase a and b isoforms,
synthesizing 2-arachidonoyl glycerol, significantly increased in definite Alzheimers (Braak stage VI), with ectopic sn-
1-diacylglycerol lipase b expression found in microglia accumulating near senile plaques and apposing CB1 cannabinoid
receptor-positive presynapses. We found that microglia, expressing two 2-arachidonoyl glycerol-degrading enzymes, serine
hydrolase a/b-hydrolase domain-containing 6 and monoacylglycerol lipase, begin to surround senile plaques in probable
Alzheimers disease (Braak stage III). However, Alzheimers pathology differentially impacts serine hydrolase a/b-hydrolase
domain-containing 6 and monoacylglycerol lipase in hippocampal neurons: serine hydrolase a/b-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 CB1 cannabinoid receptor-positive presynapses. Subcellular fractionation
revealed impaired monoacylglycerol lipase recruitment to biological membranes in post-mortem Alzheimers tissues,
suggesting that disease progression slows the termination of 2-arachidonoyl glycerol signalling. We have experimentally confirmed
that altered 2-arachidonoyl glycerol signalling could contribute to synapse silencing in Alzheimers disease by demonstrating
significantly prolonged depolarization-induced suppression of inhibition when superfusing mouse hippocampi with
amyloid-b. We propose that the temporal dynamics and cellular specificity of molecular rearrangements impairing
2-arachidonoyl glycerol availability and actions may differ from those of anandamide. Thus, enhanced endocannabinoid signalling,
particularly around senile plaques, can exacerbate synaptic failure in Alzheimers disease.a/b-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 CB1 cannabinoid receptor-positive presynapses. Subcellular fractionation
revealed impaired monoacylglycerol lipase recruitment to biological membranes in post-mortem Alzheimers tissues,
suggesting that disease progression slows the termination of 2-arachidonoyl glycerol signalling. We have experimentally confirmed
that altered 2-arachidonoyl glycerol signalling could contribute to synapse silencing in Alzheimers disease by demonstrating
significantly prolonged depolarization-induced suppression of inhibition when superfusing mouse hippocampi with
amyloid-b. We propose that the temporal dynamics and cellular specificity of molecular rearrangements impairing
2-arachidonoyl glycerol availability and actions may differ from those of anandamide. Thus, enhanced endocannabinoid signalling,
particularly around senile plaques, can exacerbate synaptic failure in Alzheimers disease.1 cannabinoid receptor-positive presynapses. Subcellular fractionation
revealed impaired monoacylglycerol lipase recruitment to biological membranes in post-mortem Alzheimers tissues,
suggesting that disease progression slows the termination of 2-arachidonoyl glycerol signalling. We have experimentally confirmed
that altered 2-arachidonoyl glycerol signalling could contribute to synapse silencing in Alzheimers disease by demonstrating
significantly prolonged depolarization-induced suppression of inhibition when superfusing mouse hippocampi with
amyloid-b. We propose that the temporal dynamics and cellular specificity of molecular rearrangements impairing
2-arachidonoyl glycerol availability and actions may differ from those of anandamide. Thus, enhanced endocannabinoid signalling,
particularly around senile plaques, can exacerbate synaptic failure in Alzheimers disease.b. We propose that the temporal dynamics and cellular specificity of molecular rearrangements impairing
2-arachidonoyl glycerol availability and actions may differ from those of anandamide. Thus, enhanced endocannabinoid signalling,
particularly around senile plaques, can exacerbate synaptic failure in Alzheimers disease.1 cannabinoid receptor protein levels in the hippocampi of patients with Alzheimers
disease remain unchanged relative to age-matched controls, and CB1 cannabinoid receptor-positive presynapses engulf
amyloid-b-containing senile plaques. Hippocampal protein concentrations for the sn-1-diacylglycerol lipase a and b isoforms,
synthesizing 2-arachidonoyl glycerol, significantly increased in definite Alzheimers (Braak stage VI), with ectopic sn-
1-diacylglycerol lipase b expression found in microglia accumulating near senile plaques and apposing CB1 cannabinoid
receptor-positive presynapses. We found that microglia, expressing two 2-arachidonoyl glycerol-degrading enzymes, serine
hydrolase a/b-hydrolase domain-containing 6 and monoacylglycerol lipase, begin to surround senile plaques in probable
Alzheimers disease (Braak stage III). However, Alzheimers pathology differentially impacts serine hydrolase a/b-hydrolase
domain-containing 6 and monoacylglycerol lipase in hippocampal neurons: serine hydrolase a/b-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 CB1 cannabinoid receptor-positive presynapses. Subcellular fractionation
revealed impaired monoacylglycerol lipase recruitment to biological membranes in post-mortem Alzheimers tissues,
suggesting that disease progression slows the termination of 2-arachidonoyl glycerol signalling. We have experimentally confirmed
that altered 2-arachidonoyl glycerol signalling could contribute to synapse silencing in Alzheimers disease by demonstrating
significantly prolonged depolarization-induced suppression of inhibition when superfusing mouse hippocampi with
amyloid-b. We propose that the temporal dynamics and cellular specificity of molecular rearrangements impairing
2-arachidonoyl glycerol availability and actions may differ from those of anandamide. Thus, enhanced endocannabinoid signalling,
particularly around senile plaques, can exacerbate synaptic failure in Alzheimers disease.a/b-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 CB1 cannabinoid receptor-positive presynapses. Subcellular fractionation
revealed impaired monoacylglycerol lipase recruitment to biological membranes in post-mortem Alzheimers tissues,
suggesting that disease progression slows the termination of 2-arachidonoyl glycerol signalling. We have experimentally confirmed
that altered 2-arachidonoyl glycerol signalling could contribute to synapse silencing in Alzheimers disease by demonstrating
significantly prolonged depolarization-induced suppression of inhibition when superfusing mouse hippocampi with
amyloid-b. We propose that the temporal dynamics and cellular specificity of molecular rearrangements impairing
2-arachidonoyl glycerol availability and actions may differ from those of anandamide. Thus, enhanced endocannabinoid signalling,
particularly around senile plaques, can exacerbate synaptic failure in Alzheimers disease.1 cannabinoid receptor-positive presynapses. Subcellular fractionation
revealed impaired monoacylglycerol lipase recruitment to biological membranes in post-mortem Alzheimers tissues,
suggesting that disease progression slows the termination of 2-arachidonoyl glycerol signalling. We have experimentally confirmed
that altered 2-arachidonoyl glycerol signalling could contribute to synapse silencing in Alzheimers disease by demonstrating
significantly prolonged depolarization-induced suppression of inhibition when superfusing mouse hippocampi with
amyloid-b. We propose that the temporal dynamics and cellular specificity of molecular rearrangements impairing
2-arachidonoyl glycerol availability and actions may differ from those of anandamide. Thus, enhanced endocannabinoid signalling,
particularly around senile plaques, can exacerbate synaptic failure in Alzheimers disease.b. We propose that the temporal dynamics and cellular specificity of molecular rearrangements impairing
2-arachidonoyl glycerol availability and actions may differ from those of anandamide. Thus, enhanced endocannabinoid signalling,
particularly around senile plaques, can exacerbate synaptic failure in Alzheimers disease.1 cannabinoid receptor-positive presynapses engulf
amyloid-b-containing senile plaques. Hippocampal protein concentrations for the sn-1-diacylglycerol lipase a and b isoforms,
synthesizing 2-arachidonoyl glycerol, significantly increased in definite Alzheimers (Braak stage VI), with ectopic sn-
1-diacylglycerol lipase b expression found in microglia accumulating near senile plaques and apposing CB1 cannabinoid
receptor-positive presynapses. We found that microglia, expressing two 2-arachidonoyl glycerol-degrading enzymes, serine
hydrolase a/b-hydrolase domain-containing 6 and monoacylglycerol lipase, begin to surround senile plaques in probable
Alzheimers disease (Braak stage III). However, Alzheimers pathology differentially impacts serine hydrolase a/b-hydrolase
domain-containing 6 and monoacylglycerol lipase in hippocampal neurons: serine hydrolase a/b-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 CB1 cannabinoid receptor-positive presynapses. Subcellular fractionation
revealed impaired monoacylglycerol lipase recruitment to biological membranes in post-mortem Alzheimers tissues,
suggesting that disease progression slows the termination of 2-arachidonoyl glycerol signalling. We have experimentally confirmed
that altered 2-arachidonoyl glycerol signalling could contribute to synapse silencing in Alzheimers disease by demonstrating
significantly prolonged depolarization-induced suppression of inhibition when superfusing mouse hippocampi with
amyloid-b. We propose that the temporal dynamics and cellular specificity of molecular rearrangements impairing
2-arachidonoyl glycerol availability and actions may differ from those of anandamide. Thus, enhanced endocannabinoid signalling,
particularly around senile plaques, can exacerbate synaptic failure in Alzheimers disease.a/b-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 CB1 cannabinoid receptor-positive presynapses. Subcellular fractionation
revealed impaired monoacylglycerol lipase recruitment to biological membranes in post-mortem Alzheimers tissues,
suggesting that disease progression slows the termination of 2-arachidonoyl glycerol signalling. We have experimentally confirmed
that altered 2-arachidonoyl glycerol signalling could contribute to synapse silencing in Alzheimers disease by demonstrating
significantly prolonged depolarization-induced suppression of inhibition when superfusing mouse hippocampi with
amyloid-b. We propose that the temporal dynamics and cellular specificity of molecular rearrangements impairing
2-arachidonoyl glycerol availability and actions may differ from those of anandamide. Thus, enhanced endocannabinoid signalling,
particularly around senile plaques, can exacerbate synaptic failure in Alzheimers disease.1 cannabinoid receptor-positive presynapses. Subcellular fractionation
revealed impaired monoacylglycerol lipase recruitment to biological membranes in post-mortem Alzheimers tissues,
suggesting that disease progression slows the termination of 2-arachidonoyl glycerol signalling. We have experimentally confirmed
that altered 2-arachidonoyl glycerol signalling could contribute to synapse silencing in Alzheimers disease by demonstrating
significantly prolonged depolarization-induced suppression of inhibition when superfusing mouse hippocampi with
amyloid-b. We propose that the temporal dynamics and cellular specificity of molecular rearrangements impairing
2-arachidonoyl glycerol availability and actions may differ from those of anandamide. Thus, enhanced endocannabinoid signalling,
particularly around senile plaques, can exacerbate synaptic failure in Alzheimers disease.b. We propose that the temporal dynamics and cellular specificity of molecular rearrangements impairing
2-arachidonoyl glycerol availability and actions may differ from those of anandamide. Thus, enhanced endocannabinoid signalling,
particularly around senile plaques, can exacerbate synaptic failure in Alzheimers disease.b-containing senile plaques. Hippocampal protein concentrations for the sn-1-diacylglycerol lipase a and b isoforms,
synthesizing 2-arachidonoyl glycerol, significantly increased in definite Alzheimers (Braak stage VI), with ectopic sn-
1-diacylglycerol lipase b expression found in microglia accumulating near senile plaques and apposing CB1 cannabinoid
receptor-positive presynapses. We found that microglia, expressing two 2-arachidonoyl glycerol-degrading enzymes, serine
hydrolase a/b-hydrolase domain-containing 6 and monoacylglycerol lipase, begin to surround senile plaques in probable
Alzheimers disease (Braak stage III). However, Alzheimers pathology differentially impacts serine hydrolase a/b-hydrolase
domain-containing 6 and monoacylglycerol lipase in hippocampal neurons: serine hydrolase a/b-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 CB1 cannabinoid receptor-positive presynapses. Subcellular fractionation
revealed impaired monoacylglycerol lipase recruitment to biological membranes in post-mortem Alzheimers tissues,
suggesting that disease progression slows the termination of 2-arachidonoyl glycerol signalling. We have experimentally confirmed
that altered 2-arachidonoyl glycerol signalling could contribute to synapse silencing in Alzheimers disease by demonstrating
significantly prolonged depolarization-induced suppression of inhibition when superfusing mouse hippocampi with
amyloid-b. We propose that the temporal dynamics and cellular specificity of molecular rearrangements impairing
2-arachidonoyl glycerol availability and actions may differ from those of anandamide. Thus, enhanced endocannabinoid signalling,
particularly around senile plaques, can exacerbate synaptic failure in Alzheimers disease.a/b-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 CB1 cannabinoid receptor-positive presynapses. Subcellular fractionation
revealed impaired monoacylglycerol lipase recruitment to biological membranes in post-mortem Alzheimers tissues,
suggesting that disease progression slows the termination of 2-arachidonoyl glycerol signalling. We have experimentally confirmed
that altered 2-arachidonoyl glycerol signalling could contribute to synapse silencing in Alzheimers disease by demonstrating
significantly prolonged depolarization-induced suppression of inhibition when superfusing mouse hippocampi with
amyloid-b. We propose that the temporal dynamics and cellular specificity of molecular rearrangements impairing
2-arachidonoyl glycerol availability and actions may differ from those of anandamide. Thus, enhanced endocannabinoid signalling,
particularly around senile plaques, can exacerbate synaptic failure in Alzheimers disease.1 cannabinoid receptor-positive presynapses. Subcellular fractionation
revealed impaired monoacylglycerol lipase recruitment to biological membranes in post-mortem Alzheimers tissues,
suggesting that disease progression slows the termination of 2-arachidonoyl glycerol signalling. We have experimentally confirmed
that altered 2-arachidonoyl glycerol signalling could contribute to synapse silencing in Alzheimers disease by demonstrating
significantly prolonged depolarization-induced suppression of inhibition when superfusing mouse hippocampi with
amyloid-b. We propose that the temporal dynamics and cellular specificity of molecular rearrangements impairing
2-arachidonoyl glycerol availability and actions may differ from those of anandamide. Thus, enhanced endocannabinoid signalling,
particularly around senile plaques, can exacerbate synaptic failure in Alzheimers disease.b. We propose that the temporal dynamics and cellular specificity of molecular rearrangements impairing
2-arachidonoyl glycerol availability and actions may differ from those of anandamide. Thus, enhanced endocannabinoid signalling,
particularly around senile plaques, can exacerbate synaptic failure in Alzheimers disease.