Specialized pro-resolving lipid mediators including maresin 1 mediate resolution but the levels of these are reduced in Alzheimer's disease brain, suggesting that they constitute a novel target for the treatment o...Specialized pro-resolving lipid mediators including maresin 1 mediate resolution but the levels of these are reduced in Alzheimer's disease brain, suggesting that they constitute a novel target for the treatment of Alzheimer's disease to prevent/stop inflammation and combat disease pathology. Therefore, it is important to clarify whether they counteract the expression of genes and proteins induced by amyloid-β. With this objective, we analyzed the relevance of human monocyte–derived microglia for in vitro modeling of neuroinflammation and its resolution in the context of Alzheimer's disease and investigated the pro-resolving bioactivity of maresin 1 on amyloid-β42–induced Alzheimer's disease–like inflammation. Analysis of RNA-sequencing data and secreted proteins in supernatants from the monocyte-derived microglia showed that the monocyte-derived microglia resembled Alzheimer's disease–like neuroinflammation in human brain microglia after incubation with amyloid-β42. Maresin 1 restored homeostasis by down-regulating inflammatory pathway related gene expression induced by amyloid-β42 in monocyte-derived microglia, protection of maresin 1 against the effects of amyloid-β42 is mediated by a re-balancing of inflammatory transcriptional networks in which modulation of gene transcription in the nuclear factor-kappa B pathway plays a major part. We pinpointed molecular targets that are associated with both neuroinflammation in Alzheimer's disease and therapeutic targets by maresin 1. In conclusion, monocyte-derived microglia represent a relevant in vitro microglial model for studies on Alzheimer's disease-like inflammation and drug response for individual patients. Maresin 1 ameliorates amyloid-β42–induced changes in several genes of importance in Alzheimer's disease, highlighting its potential as a therapeutic target for Alzheimer's disease.展开更多
Humans have been using Cannabis and its extracts for a few thousand years as a medicinal and recreational drug. How- ever, the chemical component in Cannabis sativa, △9-tet- rahydrocannabinol （△9-THC）, an exogenou...Humans have been using Cannabis and its extracts for a few thousand years as a medicinal and recreational drug. How- ever, the chemical component in Cannabis sativa, △9-tet- rahydrocannabinol （△9-THC）, an exogenous cannabinoid, remained unknown until it was isolated and identified as the main psychoactive ingredient （Gaoni and Mechoulam, 1964）.展开更多
The presynaptic active zone is a dynamic structure that orchestrates regulated release of neurotrans- mitters. Developmental and aging processes, and changes in neuronal network activity can all modulate the number, s...The presynaptic active zone is a dynamic structure that orchestrates regulated release of neurotrans- mitters. Developmental and aging processes, and changes in neuronal network activity can all modulate the number, size and composition of active zone and thereby synaptic efficacy. However, very little is known about the mechanism that controls the structural stability of active zone. By study- ing a model synapse, the Drosophila neuromuscular iunction, our recent work shed light on how two scaffolding proteins at the active zone regulate active zone stability by promoting a localized dephos- phorylation event at the nerve terminal. Here we discuss the major insights from our findings and their implications for future research.展开更多
Endocannabinoids are endogenous lipid mediators contributing to a variety of physiological,pharmacological,and pathological processes primarily through acting on cannabinoid receptors(CB1R and CB2R),which are targets...Endocannabinoids are endogenous lipid mediators contributing to a variety of physiological,pharmacological,and pathological processes primarily through acting on cannabinoid receptors(CB1R and CB2R),which are targets ofΔ9-tetrahydrocannabinol(Δ9-THC),the major psychoactive ingredient in marijuana.[1]Although N-arachidonoyl ethanolamide is the first identified endocannabinoid,2-arachidonoylglycerol(2-AG),the second identified endocannabinoid,is the most abundant ligand produced in our body and a full agonist for CB1R and CB2R.^([2])It has been well recognized that 2-AG is a retrograde messenger modulating synaptic transmission and plasticity at both inhibitory GABAergic and excitatory glutamatergic synapses in the brain.展开更多
基金supported by the China Scholarship Council(to YW)the Swedish Research Council,No.2018-02601(to MS)+7 种基金the Alzheimer Foundation,No.AF-980695(to MS)the Stockholm County Council,No.RS2020-0731(to MS)the Foundation of Old Servants(to MS)the Gun and Bertil Stohne Foundation(to MS)the?hlén Foundation,No.233055(to MS)The Swedish Fund for Research without Animal Experiments(to MS)the Swedish Dementia Foundation(to MS)the Brain foundation,No.FO2022-0131(to MS)。
文摘Specialized pro-resolving lipid mediators including maresin 1 mediate resolution but the levels of these are reduced in Alzheimer's disease brain, suggesting that they constitute a novel target for the treatment of Alzheimer's disease to prevent/stop inflammation and combat disease pathology. Therefore, it is important to clarify whether they counteract the expression of genes and proteins induced by amyloid-β. With this objective, we analyzed the relevance of human monocyte–derived microglia for in vitro modeling of neuroinflammation and its resolution in the context of Alzheimer's disease and investigated the pro-resolving bioactivity of maresin 1 on amyloid-β42–induced Alzheimer's disease–like inflammation. Analysis of RNA-sequencing data and secreted proteins in supernatants from the monocyte-derived microglia showed that the monocyte-derived microglia resembled Alzheimer's disease–like neuroinflammation in human brain microglia after incubation with amyloid-β42. Maresin 1 restored homeostasis by down-regulating inflammatory pathway related gene expression induced by amyloid-β42 in monocyte-derived microglia, protection of maresin 1 against the effects of amyloid-β42 is mediated by a re-balancing of inflammatory transcriptional networks in which modulation of gene transcription in the nuclear factor-kappa B pathway plays a major part. We pinpointed molecular targets that are associated with both neuroinflammation in Alzheimer's disease and therapeutic targets by maresin 1. In conclusion, monocyte-derived microglia represent a relevant in vitro microglial model for studies on Alzheimer's disease-like inflammation and drug response for individual patients. Maresin 1 ameliorates amyloid-β42–induced changes in several genes of importance in Alzheimer's disease, highlighting its potential as a therapeutic target for Alzheimer's disease.
基金supported by National Institutes of Health grants NS076815
文摘Humans have been using Cannabis and its extracts for a few thousand years as a medicinal and recreational drug. How- ever, the chemical component in Cannabis sativa, △9-tet- rahydrocannabinol （△9-THC）, an exogenous cannabinoid, remained unknown until it was isolated and identified as the main psychoactive ingredient （Gaoni and Mechoulam, 1964）.
文摘The presynaptic active zone is a dynamic structure that orchestrates regulated release of neurotrans- mitters. Developmental and aging processes, and changes in neuronal network activity can all modulate the number, size and composition of active zone and thereby synaptic efficacy. However, very little is known about the mechanism that controls the structural stability of active zone. By study- ing a model synapse, the Drosophila neuromuscular iunction, our recent work shed light on how two scaffolding proteins at the active zone regulate active zone stability by promoting a localized dephos- phorylation event at the nerve terminal. Here we discuss the major insights from our findings and their implications for future research.
基金financed by National Institutes of Health grants(No.NS076815).
文摘Endocannabinoids are endogenous lipid mediators contributing to a variety of physiological,pharmacological,and pathological processes primarily through acting on cannabinoid receptors(CB1R and CB2R),which are targets ofΔ9-tetrahydrocannabinol(Δ9-THC),the major psychoactive ingredient in marijuana.[1]Although N-arachidonoyl ethanolamide is the first identified endocannabinoid,2-arachidonoylglycerol(2-AG),the second identified endocannabinoid,is the most abundant ligand produced in our body and a full agonist for CB1R and CB2R.^([2])It has been well recognized that 2-AG is a retrograde messenger modulating synaptic transmission and plasticity at both inhibitory GABAergic and excitatory glutamatergic synapses in the brain.
