Rôle et potentialités thérapeutiques des cellules T régulatrices dans la physiopathologie de la maladie d'Alzheimer

Alzheimer’s Disease (AD) is a neurodegenerative disorder characterized by progressive loss of memory and cognitive functions. Accumulation of Aβ peptide is considered the initiating cause of pathogenic lesions, and immunotherapy strategies targeting Aβ represent promising therapeutic approaches. Vaccination against Aβ provided encouraging results in experimental mouse models and, to a lesser extent, in a subsequent clinical trial (AN1792). Although the AN1792 trial had to be interrupted due to meningoencephalitis attributed to pro-inflammatory T cell responses in 6% of the patients, preclinical murine models did not show evidence of T cell-related side effects. In addition, several reports suggest that Aβ-specific CD4+ T cells may be implicated in the natural course of AD and could have a strong therapeutic potential as well, pointing out the need for better understanding the role and regulation of T cell responses to Aβ. We previously showed that regulatory T cells (Tregs) control Aβ-specific CD4+ T cell responses in physiological and pathological settings upon vaccination. The aim of this work was to analyze the impact of Tregs on the natural course of the disease progression in a mouse model of AD. Early transient depletion of Tregs accelerated the onset of cognitive deficits in APPPS1 mice. This result was correlated with less recruitment of microglia towards amyloid deposits and altered disease-related gene expression profile. Conversely, Tregs selectively amplifying resulted in higher numbers of plaque-associated microglia and improved cognitive functions in APPPS1 mice. These data suggest a beneficial role of Tregs in the pathophysiology of AD by modulating microglial response. Our study highlithts the therapeutic potential of Treg-based immunotherapies in AD.La MA est caractérisée par une altération progressive des fonctions cognitives, et définie par les "dégénérescences neurofibrillaires", les "plaques séniles" et une neuroinflammation impliquant les cellules microgliales. L’immunothérapie constitue une approche thérapeutique prometteuse dans la MA. Un premier essai clinique de vaccination anti-Aβ a été arrêté après la survenue de 6% de cas de méningoencéphalites imputés à l’activation de réponses T anti-Aβ pro-inflammatoires. Cependant, des études récentes suggèrent un effet bénéfique de certaines populations de cellules T CD4+ anti-Aβ. L'ensemble de ces données suggère des rôles complexes de différentes réponses lymphocytaires T au cours de la MA, et soulignent la nécessité de mieux comprendre leur implication dans la maladie et les mécanismes de leur régulation. L’objectif de ce travail a été d’étudier l’impact des Tregs sur la progression de la maladie dans un modèle murin APPPS1. Les résultats montrent que la déplétion transitoire des Tregs accélère l’apparition des troubles cognitifs, sans altérer la pathologie amyloïde. Ces observations sont corrélées avec une réduction du recrutement des cellules microgliales autour des plaques Aβ et une altération du profil d’expression, dans le cerveau des souris, de certains gènes impliqués dans la maladie. A l’inverse, l’amplification sélective des réponses Tregs entraine une augmentation du recrutement des cellules microgliales autour des plaques et une amélioration des fonctions cognitives. L’ensemble de ces résultats suggère un rôle bénéfique des Tregs au cours de la maladie d’Alzheimer et encourage le développement d’approches d’immunothérapie basées sur leur modulation

Immunodepression and Immunosuppression During Aging

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Microglia jointly degrade fibrillar alpha-synuclein cargo by distribution through tunneling nanotubes

Microglia are the CNS resident immune cells that react to misfolded proteins through pattern recognition receptor ligation and activation of inflammatory pathways. Here, we studied how microglia handle and cope with alpha-synuclein (alpha-syn) fibrils and their clearance. We found that microglia exposed to alpha-syn establish a cellular network through the formation of F-actin-dependent intercellular connections, which transfer alpha-syn from overloaded microglia to neighboring naive microglia where the alpha-syn cargo got rapidly and effectively degraded. Lowering the alpha-syn burden attenuated the inflammatory profile of microglia and improved their survival. This degradation strategy was compromised in cells carrying the LRRK2 G2019S mutation. We confirmed the intercellular transfer of alpha-syn assemblies in microglia using organotypic slice cultures, 2-photon microscopy, and neuropathology of patients. Together, these data identify a mechanism by which microglia create an on-demand functional network in order to improve pathogenic alpha-syn clearance

Role and therapeutic potential of T regulatory cells in pathophysiology of Alzheimer's disease

La MA est caractérisée par une altération progressive des fonctions cognitives, et définie par les "dégénérescences neurofibrillaires", les "plaques séniles" et une neuroinflammation impliquant les cellules microgliales. L’immunothérapie constitue une approche thérapeutique prometteuse dans la MA. Un premier essai clinique de vaccination anti-Aβ a été arrêté après la survenue de 6% de cas de méningoencéphalites imputés à l’activation de réponses T anti-Aβ pro-inflammatoires. Cependant, des études récentes suggèrent un effet bénéfique de certaines populations de cellules T CD4+ anti-Aβ. L'ensemble de ces données suggère des rôles complexes de différentes réponses lymphocytaires T au cours de la MA, et soulignent la nécessité de mieux comprendre leur implication dans la maladie et les mécanismes de leur régulation. L’objectif de ce travail a été d’étudier l’impact des Tregs sur la progression de la maladie dans un modèle murin APPPS1. Les résultats montrent que la déplétion transitoire des Tregs accélère l’apparition des troubles cognitifs, sans altérer la pathologie amyloïde. Ces observations sont corrélées avec une réduction du recrutement des cellules microgliales autour des plaques Aβ et une altération du profil d’expression, dans le cerveau des souris, de certains gènes impliqués dans la maladie. A l’inverse, l’amplification sélective des réponses Tregs entraine une augmentation du recrutement des cellules microgliales autour des plaques et une amélioration des fonctions cognitives. L’ensemble de ces résultats suggère un rôle bénéfique des Tregs au cours de la maladie d’Alzheimer et encourage le développement d’approches d’immunothérapie basées sur leur modulation.Alzheimer’s Disease (AD) is a neurodegenerative disorder characterized by progressive loss of memory and cognitive functions. Accumulation of Aβ peptide is considered the initiating cause of pathogenic lesions, and immunotherapy strategies targeting Aβ represent promising therapeutic approaches. Vaccination against Aβ provided encouraging results in experimental mouse models and, to a lesser extent, in a subsequent clinical trial (AN1792). Although the AN1792 trial had to be interrupted due to meningoencephalitis attributed to pro-inflammatory T cell responses in 6% of the patients, preclinical murine models did not show evidence of T cell-related side effects. In addition, several reports suggest that Aβ-specific CD4+ T cells may be implicated in the natural course of AD and could have a strong therapeutic potential as well, pointing out the need for better understanding the role and regulation of T cell responses to Aβ. We previously showed that regulatory T cells (Tregs) control Aβ-specific CD4+ T cell responses in physiological and pathological settings upon vaccination. The aim of this work was to analyze the impact of Tregs on the natural course of the disease progression in a mouse model of AD. Early transient depletion of Tregs accelerated the onset of cognitive deficits in APPPS1 mice. This result was correlated with less recruitment of microglia towards amyloid deposits and altered disease-related gene expression profile. Conversely, Tregs selectively amplifying resulted in higher numbers of plaque-associated microglia and improved cognitive functions in APPPS1 mice. These data suggest a beneficial role of Tregs in the pathophysiology of AD by modulating microglial response. Our study highlithts the therapeutic potential of Treg-based immunotherapies in AD

Neuroinflammatory responses in Alzheimer's disease.

peer reviewedNeuroinflammatory responses in Alzheimer's disease (AD) are complex and not fully understood. They involve various cellular and molecular players and associate interaction between the central nervous system (CNS) and the periphery. Amyloid peptides within the senile plaques and abnormally phosphorylated tau in neurofibrillary tangles are able to initiate inflammatory responses, in brain of AD patients and in mouse models of this disease. The outcome of these responses on the pathophysiology of AD depends on several factors and can be either beneficial or detrimental. Thus, understanding the role of neuroinflammation in AD could help to develop safer and more efficient therapeutic strategies. This review discusses recent knowledge on microglia responses toward amyloid and tau pathology in AD, focusing on the role of Toll-like receptors and NOD-like receptor protein 3 (NLRP3) inflammasome activation in microglial cells

Soluble Aβ oligomers and protofibrils induce NLRP3 inflammasome activation in microglia

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder causing memory loss, language problems and behavioural disturbances. AD is associated with the accumulation of fibrillar amyloid-β (Aβ) and the formation of neurofibrillary tau tangles. Fibrillar Aβ itself represents a danger-associated molecular pattern, which is recognized by specific microglial receptors. One of the key players is formation of the NOD-, LRR- and pyrin domain-containing 3 (NLRP3) inflammasome, whose activation has been demonstrated in AD patient brains and transgenic animal models of AD. Here, we investigated whether Aβ oligomers or protofibrils that represent lower molecular aggregates prior to Aβ deposition are able to activate the NLRP3 inflammasome and subsequent interleukin-1 beta (IL-1β) release by microglia. In our study, we used Aβ preparations of different sizes: small oligomers and protofibrils of which the structure was confirmed by atomic force microscopy. Primary microglial cells from C57BL/6 mice were treated with the respective Aβ preparations and NLRP3 inflammasome activation, represented by caspase-1 cleavage, IL-1β production, and apoptosis-associated speck-like protein containing a CARD speck formation was analysed. Both protofibrils and low molecular weight Aβ aggregates induced a significant increase in IL-1β release. Inflammasome activation was confirmed by apoptosis-associated speck-like protein containing a CARD speck formation and detection of active caspase-1. The NLRP3 inflammasome inhibitor MCC950 completely inhibited the Aβ-induced immune response. Our results show that the NLRP3 inflammasome is activated not only by fibrillar Aβ aggregates as reported before, but also by lower molecular weight Aβ oligomers and protofibrils, highlighting the possibility that microglial activation by these Aβ species may initiate innate immune responses in the central nervous system prior to the onset of Aβ deposition