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001-es BibID:BIBFORM019984
Első szerző:Halleskog, Carina
Cím:WNT signaling in activated microglia is proinflammatory / Carina Halleskog, Jan Mulder, Jenny Dahlström, Ken Mackie, Tibor Hortobágyi, Heikki Tanila, Lakshman Kumar Puli, Katrin Färber, Tibor Harkany, Gunnar Schulte
Dátum:2011
ISSN:0894-1491
Megjegyzések:Microglia activation is central to the neuroinflammation associated with neurological and neurodegenerative diseases, particularly because activated microglia are often a source of proinflammatory cytokines. Despite decade-long research, the molecular cascade of proinflammatory transformation of microglia in vivo remains largely elusive. Here, we report increased β-catenin expression, a central intracellular component of WNT signaling, in microglia undergoing a proinflammatory morphogenic transformation under pathogenic conditions associated with neuroinflammation such as Alzheimer's disease. We substantiate disease-associated β-catenin signaling in microglia in vivo by showing age-dependent β-catenin accumulation in mice with Alzheimer's-like pathology (APdE9). In cultured mouse microglia expressing the WNT receptors Frizzled FZD(4,5,7,8) and LDL receptor-related protein 5/6 (LRP5/6), we find that WNT-3A can stabilize β-catenin. WNT-3A dose dependently induces LRP6 phosphorylation with downstream activation of disheveled, β-catenin stabilization, and nuclear import. Gene-expression profiling reveals that WNT-3A stimulation specifically increases the expression of proinflammatory immune response genes in microglia and exacerbates the release of de novo IL-6, IL-12, and tumor necrosis factor α. In summary, our data suggest that the WNT family of lipoglycoproteins can instruct proinflammatory microglia transformation and emphasize the pathogenic significance of β-catenin-signaling networks in this cell type.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Glia. - 59 : 1 (2011), p. 119-131. -
További szerzők:Mulder, Jan Dahlström, Jenny Mackie, Ken Hortobágyi Tibor (1965-) (patológus) Tanila, Heikki Kumar Puli, Lakshman Färber, Katrin Harkány Tibor Schulte, Gunnar
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001-es BibID:BIBFORM019971
Első szerző:Mulder, Jan
Cím:Molecular reorganization of endocannabinoid signalling in Alzheimer's disease / Jan Mulder, Misha Zilberter, Susana J. Pasquaré, Alán Alpár, Gunnar Schulte, Samira G. Ferreira, Attila Köfalvi, Ana M. Martín-Moreno, Erik Keimpema, Heikki Tanila, Masahiko Watanabe, Ken Mackie, Tibor Hortobágyi, Maria L. de Ceballos, Tibor Harkany
Dátum:2011
ISSN:0006-8950
Megjegyzések: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 contribute to synapse silencing in Alzheimer's disease by demonstrating significantly prolonged depolarization-induced suppression of inhibition when superfusing mouse hippocampi with amyloid-β. 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 Alzheimer's disease.
Tárgyszavak:Orvostudományok Klinikai orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Brain. - 134 : 4 (2011), p. 1041-1060. -
További szerzők:Zilberter, Misha Pasquaré, Susana J. Alpár Alán Schulte, Gunnar Ferreira, Samira G. Köfalvi Attila Martín-Moreno, Ana M. Keimpema, Erik Tanila, Heikki Watanabe, Masahiko Mackie, Ken Hortobágyi Tibor (1965-) (patológus) de Ceballos, Maria L. Harkány Tibor
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