N-3 PUFAs and neuroinflammatory processes in cognitive disorders

Le développement d’approches nutritionnelles pertinentes pour prévenir et retarder l’apparition du déclin cognitif est un enjeu important, compte tenu du vieillissement de la population et de l’augmentation de l’incidence des maladies neurodégénératives. Les processus neuro-inflammatoires contribuent aux mécanismes neuropathologiques impliqués dans les troubles neurodégénératifs et de la cognition. Des données récentes indiquent l’importance des acides gras polyinsaturés n-3 alimentaires dans le maintien des performances mnésiques et la régulation de la neuroinflammation liée à l’âge ou à la maladie d’Alzheimer. Dans cette revue, seront présentées des données récentes sur les liens existants entre le statut nutritionnel en acides gras polyinsaturés n-3, les processus neuro-inflammatoires et les troubles cognitifs associés, ainsi que les mécanismes qui pourraient être impliqués dans les effets protecteurs de ces acides gras.With the ageing population and increased cases of neurodegenerative diseases, there is a crucial need for the development of new nutritional approaches to prevent and delay the onset of cognitive decline. Neuroinflammatory processes contribute to neuronal damage that underpins neurodegenerative disorders. Growing evidence sheds light on the use of dietary n-3 long chain polyunsaturated fatty acids to improve cognitive performances and reduce the neuroinflammatory responses occurring with age and neurodegenerative pathologies. This review will summarise the most recent information related to the impact and mechanisms underlying the neuroinflammatory processes in cognitive disorders. We will also discuss the mechanisms underlying n-3 polyunsaturated fatty acids effect on neuroinflammation and memory decline

Role of n-3 PUFAs in inflammation via resolvin biosynthesis

Le rôle des AGPI n-3 a considérablement augmenté ces dernières années, en particulier dans les processus inflammatoires en raison de leurs propriétés anti-inflammatoires. L’inflammation est une réponse protectrice de l’organisme visant à contrôler l’infection et à favoriser la réparation des tissus. Cependant, une inflammation excessive peut avoir de graves conséquences au niveau des tissus. C’est notamment le cas pour le cerveau pour lequel les conséquences fonctionnelles de la neuro-inflammation comprennent des altérations de la cognition, de l’affect et du comportement, conduisant à un impact négatif sur la qualité de vie et le bien-être des patients (Dantzer, 2001, 2008). Par conséquent, limiter l’inflammation dans le cerveau représente une véritable stratégie dans le cadre de la prévention et du traitement des maladies neuro-inflammatoires. Des données récentes montrent que les AGPI n-3 exercent leurs propriétés anti-inflammatoires en partie via la synthèse de médiateurs lipidiques spécialisés tels que les résolvines, qui participent activement à réduire la réponse inflammatoire. Cette revue rappelle d’abord les concepts de base de la réponse inflammatoire et le rôle des AGPI n-3 dans ce processus et présente ensuite la biosynthèse, les voies de signalisation et le rôle des résolvines.The role of n-3 PUFAs has gained more importance these last decades, especially in inflammatory processes because they can display anti-inflammatory properties. Inflammation is a protective response of the body in controlling infection and promoting tissue repair. However, excessive inflammation can cause local tissue damage. This is especially the case for the brain for which the functional consequences of neuroinflammation include alterations in cognition, affect and behavior leading to a negative impact on the quality of life and well-being of patients (Dantzer, 2001, 2008). Hence, limiting the inflammation in the brain is a real strategy for neuroinflammatory disease therapy and treatment. Recent data show that n-3 PUFAs exert anti-inflammatory properties in part through the synthesis of specialized pro-resolving mediators such as resolvins that actively turned off the inflammatory response. This review first outlines basic concepts of neuroinflammation and the role of n-3 PUFAs in this process and then summarizes the biosynthesis, signaling pathways and role of resolvins

Inhibiting microglia expansion prevents diet-induced hypothalamic and peripheral inflammation

Cell proliferation and neuroinflammation in the adult hypothalamus may contribute to the pathogenesis of obesity. We tested whether the intertwining of these two processes plays a role in the metabolic changes caused by 3 weeks of a high-saturated fat diet (HFD) consumption. Compared with chow-fed mice, HFD-fed mice had a rapid increase in body weight and fat mass and specifically showed an increased number of microglia in the arcuate nucleus (ARC) of the hypothalamus. Microglia expansion required the adequate presence of fats and carbohydrates in the diet because feeding mice a very high-fat, very low-carbohydrate diet did not affect cell proliferation. Blocking HFD-induced cell proliferation by central delivery of the antimitotic drug arabinofuranosyl cytidine (AraC) blunted food intake, body weight gain, and adiposity. AraC treatment completely prevented the increase in number of activated microglia in the ARC, the expression of the proinflammatory cytokine tumor necrosis factor-? in microglia, and the recruitment of the nuclear factor-?B pathway while restoring hypothalamic leptin sensitivity. Central blockade of cell proliferation also normalized circulating levels of the cytokines leptin and interleukin 1? and decreased peritoneal proinflammatory CD86 immunoreactive macrophage number. These findings suggest that inhibition of diet-dependent microglia expansion hinders body weight gain while preventing central and peripheral inflammatory responses due to caloric overload.Dissection des mécanismes hypothalamiques impliqués dans la détection du statut nutritionnel et régulation de la prise alimentaire via les interactions entre mTORC1, les mélanocortines et les endocannabinoïdes

Microglia modulates hippocampal synaptic transmission and sleep duration along the light/dark cycle

Microglia, the brain's resident macrophages, actively contributes to the homeostasis of cerebral parenchyma by sensing neuronal activity and supporting synaptic remodeling and plasticity. While several studies demonstrated different roles for astrocytes in sleep, the contribution of microglia in the regulation of sleep/wake cycle and in the modulation of synaptic activity in the different day phases has not been deeply investigated. Using light as a zeitgeber cue, we studied the effects of microglial depletion with the colony stimulating factor-1 receptor antagonist PLX5622 on the sleep/wake cycle and on hippocampal synaptic transmission in male mice. Our data demonstrate that almost complete microglial depletion increases the duration of NREM sleep and reduces the hippocampal excitatory neurotransmission. The fractalkine receptor CX3CR1 plays a relevant role in these effects, because cx3cr1GFP/GFP mice recapitulate what found in PLX5622-treated mice. Furthermore, during the light phase, microglia express lower levels of cx3cr1 and a reduction of cx3cr1 expression is also observed when cultured microglial cells are stimulated by ATP, a purinergic molecule released during sleep. Our findings suggest that microglia participate in the regulation of sleep, adapting their cx3cr1 expression in response to the light/dark phase, and modulating synaptic activity in a phase-dependent manner.Bordeaux Region Aquitaine Initiative for Neuroscienc

Essential omega-3 fatty acids tune microglial phagocytosis of synaptic elements in the mouse developing brain

AbstractOmega-3 fatty acids (n-3 PUFAs) are essential for the functional maturation of the brain. Westernization of dietary habits in both developed and developing countries is accompanied by a progressive reduction in dietary intake of n-3 PUFAs. Low maternal intake of n-3 PUFAs has been linked to neurodevelopmental diseases in Humans. However, the n-3 PUFAs deficiency-mediated mechanisms affecting the development of the central nervous system are poorly understood. Active microglial engulfment of synapses regulates brain development. Impaired synaptic pruning is associated with several neurodevelopmental disorders. Here, we identify a molecular mechanism for detrimental effects of low maternal n-3 PUFA intake on hippocampal development in mice. Our results show that maternal dietary n-3 PUFA deficiency increases microglia-mediated phagocytosis of synaptic elements in the rodent developing hippocampus, partly through the activation of 12/15-lipoxygenase (LOX)/12-HETE signaling, altering neuronal morphology and affecting cognitive performance of the offspring. These findings provide a mechanistic insight into neurodevelopmental defects caused by maternal n-3 PUFAs dietary deficiency.Infrastructure de Recherche Translationnelle pour les Biothérapies en NeurosciencesProgram Initiative d’Excellenc

Correction: Neuronal Hyperactivity Disturbs ATP Microgradients, Impairs Microglial Motility, and Reduces Phagocytic Receptor Expression Triggering Apoptosis/Microglial Phagocytosis Uncoupling

Correction de l'article DOI: 10.1371/journal.pbio.100246

Roles of Microglial Phagocytosis and Inflammatory Mediators in the Pathophysiology of Sleep Disorders

Sleep serves crucial learning and memory functions in both nervous and immune systems. Microglia are brain immune cells that actively maintain health through their crucial physiological roles exerted across the lifespan, including phagocytosis of cellular debris and orchestration of neuroinflammation. The past decade has witnessed an explosive growth of microglial research. Considering the recent developments in the field of microglia and sleep, we examine their possible impact on various pathological conditions associated with a gain, disruption, or loss of sleep in this focused mini-review. While there are extensive studies of microglial implication in a variety of neuropsychiatric and neurodegenerative diseases, less is known regarding their roles in sleep disorders. It is timely to stimulate new research in this emergent and rapidly growing field of investigation.Peer reviewe

Neuronal hyperactivity disturbs ATP microgradients, impairs microglial motility, and reduces phagocytic receptor expression triggering apoptosis/microglial phagocytosis uncoupling

Phagocytosis is essential to maintain tissue homeostasis in a large number of inflammatory and autoimmune diseases, but its role in the diseased brain is poorly explored. Recent findings suggest that in the adult hippocampal neurogenic niche, where the excess of newborn cells undergo apoptosis in physiological conditions, phagocytosis is efficiently executed by surveillant, ramified microglia. To test whether microglia are efficient phagocytes in the diseased brain as well, we confronted them with a series of apoptotic challenges and discovered a generalized response. When challenged with excitotoxicity in vitro (via the glutamate agonist NMDA) or inflammation in vivo (via systemic administration of bacterial lipopolysaccharides or by omega 3 fatty acid deficient diets), microglia resorted to different strategies to boost their phagocytic efficiency and compensate for the increased number of apoptotic cells, thus maintaining phagocytosis and apoptosis tightly coupled. Unexpectedly, this coupling was chronically lost in a mouse model of mesial temporal lobe epilepsy (MTLE) as well as in hippocampal tissue resected from individuals with MTLE, a major neurological disorder characterized by seizures, excitotoxicity, and inflammation. Importantly, the loss of phagocytosis/apoptosis coupling correlated with the expression of microglial proinflammatory, epileptogenic cytokines, suggesting its contribution to the pathophysiology of epilepsy. The phagocytic blockade resulted from reduced microglial surveillance and apoptotic cell recognition receptor expression and was not directly mediated by signaling through microglial glutamate receptors. Instead, it was related to the disruption of local ATP microgradients caused by the hyperactivity of the hippocampal network, at least in the acute phase of epilepsy. Finally, the uncoupling led to an accumulation of apoptotic newborn cells in the neurogenic niche that was due not to decreased survival but to delayed cell clearance after seizures. These results demonstrate that the efficiency of microglial phagocytosis critically affects the dynamics of apoptosis and urge to routinely assess the microglial phagocytic efficiency in neurodegenerative disorders

Matter

Microglia researchers are constantly looking for new targeting tools that are more precise in time and space. In this article, Guo et al. present the results of their latest study in which they develop nanoparticles capable of targeting microglia with high spatial specificity and delivering siRNAs to alter the transcriptome profile of the cells. Although certain obstacles remain, this study is very promising in the race for new tools to manipulate microglial activity locally in the brain

Roles of Microglial Phagocytosis and Inflammatory Mediators in the Pathophysiology of Sleep Disorders

Sleep serves crucial learning and memory functions in both nervous and immune systems. Microglia are brain immune cells that actively maintain health through their crucial physiological roles exerted across the lifespan, including phagocytosis of cellular debris and orchestration of neuroinflammation. The past decade has witnessed an explosive growth of microglial research. Considering the recent developments in the field of microglia and sleep, we examine their possible impact on various pathological conditions associated with a gain, disruption, or loss of sleep in this focused mini-review. While there are extensive studies of microglial implication in a variety of neuropsychiatric and neurodegenerative diseases, less is known regarding their roles in sleep disorders. It is timely to stimulate new research in this emergent and rapidly growing field of investigation