12 research outputs found
COX-2-Derived Prostaglandin E2 Produced by Pyramidal Neurons Contributes to Neurovascular Coupling in the Rodent Cerebral Cortex
International audienceVasodilatory prostaglandins play a key role in neurovascular coupling (NVC), the tight link between neuronal activity and local cerebral blood flow, but their precise identity, cellular origin and the receptors involved remain unclear. Here we show in rats that NMDA-induced vasodilation and hemodynamic responses evoked by whisker stimulation involve cyclooxygenase-2 (COX-2) activity and activation of the prostaglandin E2 (PgE(2)) receptors EP2 and EP4. Using liquid chromatography-electrospray ionization-tandem mass spectrometry, we demonstrate that PgE(2) is released by NMDA in cortical slices. The characterization of PgE2 producing cells by immunohistochemistry and single-cell reverse transcriptase-PCR revealed that pyramidal cells and not astrocytes are the main cell type equipped for PgE2 synthesis, one third expressing COX-2 systematically associated with a PgE2 synthase. Consistent with their central role in NVC, in vivo optogenetic stimulation of pyramidal cells evoked COX-2-dependent hyperemic responses in mice. These observations identify PgE2 as the main prostaglandin mediating sensory-evoked NVC, pyramidal cells as their principal source and vasodilatory EP2 and EP4 receptors as their targets
Expression et fonction des prĂ©sĂ©nilines vasculaires et exploration de lâhypothĂšse vasculaire de la Maladie dâAlzheimer
Les prĂ©sĂ©nilines PS1 et PS2 sont impliquĂ©es dans plusieurs fonctions cellulaires par lâintermĂ©diaire de leur activitĂ© protĂ©olytique ?-sĂ©crĂ©tase qui clive de nombreux substrats y compris la protĂ©ine prĂ©curseur amyloĂŻde (APP). Les mutations des prĂ©sĂ©nilines, Ă lâorigine des formes familiales de la maladie dâAlzheimer (MA), augmentent la production de peptides Ă-amyloĂŻde (AĂ) qui sâaccumulent dans le parenchyme cĂ©rĂ©bral et dans la paroi vasculaire, et affectent les signaux calciques de plusieurs types cellulaires. Le rĂ©seau vasculaire des patients atteints de la MA est affectĂ© structurellement et fonctionnellement bien avant que ne se dĂ©clarent les troubles cognitifs. De plus, les pathologies cardiovasculaires sont des facteurs de risque majeurs pour les formes sporadiques de la MA. Comme les bases molĂ©culaires de la vasculopathie liĂ©e Ă la MA ne sont pas Ă©tablies, nous avons choisi les prĂ©sĂ©nilines comme molĂ©cule cible dans le systĂšme vasculaire. Nous avons montrĂ© lâexpression des prĂ©sĂ©nilines et des protĂ©ines partenaires du complexe ?-sĂ©crĂ©tase, Nicastrine, Aph-1 et Pen-2 dans les vaisseaux cĂ©rĂ©braux et pĂ©riphĂ©riques. Lâensemble gĂ©nĂšre une activitĂ© ?-sĂ©crĂ©tase et la production de peptides AĂ pathogĂšnes dans les cellules musculaires lisses, soutenant lâhypothĂšse de lâorigine vasculaire dâAĂ dans la pathologie amyloĂŻde. De plus, les mutations de PS1 dĂ©rĂ©gulent la signalisation calcique intracellulaire des artĂšres cĂ©rĂ©brales, en augmentant lâactivitĂ© des canaux de libĂ©ration du Ca2+ activĂ©s par lâIP3 (IP3R) et la recapture du Ca2+ par les pompes du rĂ©ticulum sarco-endoplasmique Ca2+-ATPase (SERCA). La dĂ©rĂ©gulation de lâhomĂ©ostasie calcique par les prĂ©sĂ©nilines mutĂ©es pourrait avoir des consĂ©quences sur la rĂ©activitĂ© vasculaire des vaisseaux cĂ©rĂ©braux. En conclusion, nous avons mis en Ă©vidence lâimportance physiologique des prĂ©sĂ©nilines dans le rĂ©seau vasculaire et lâensemble de nos travaux permet de mieux comprendre comment les vaisseaux participent Ă lâapparition des symptĂŽmes cliniques de la MA que sont la surproduction dâAĂ et lâhypoperfusion cĂ©rĂ©brale.Presenilins PS1 and PS2 are involved in several cellular functions through their ?- secretase proteolytic activity, which cleaves many substrates including the amyloid precursor protein (APP). Mutations in presenilins genes are responsible for the majority of familial forms of Alzheimer's disease (AD). Presenilins mutations increased production of Ă-amyloid peptide (AĂ) that accumulates in the brain parenchyma and the vascular wall, and affect calcium signals in several cell types. The vasculature of patients with AD is structurally and functionally affected before cognitive impairment appearance. In addition, cardiovascular diseases are major risk factors for sporadic forms of AD. As the molecular basis of the vasculopathy associated with AD is not established, we chose presenilins as target molecule in the vascular system. We showed the expression of presenilin and protein partners of ?-secretase complex, nicastrin, Aph-1 and Pen-2 in cerebral and peripheral blood vessels. Vascular wall generate a ?-secretase activity and production of pathogenic AĂ peptides supporting the hypothesis of vascular origin of AĂ in amyloid pathology. Furthermore, PS1 mutations disturb intracellular calcium signalling in cerebral arteries by first increasing channel activity of Ca2+ release activated by IP3 (IP3R) and second increasing reuptake of Ca2+ by Sarco/Endoplasmic Reticulum Ca2+-ATPase pump (SERCA). Dysregulation of calcium homeostasis by the mutant presenilins might affect vascular reactivity of cerebral vessels. In conclusion, we demonstrated the physiological importance of presenilins in the vascular network and our studies provide new insight on how cerebral blood vessels are involved in the onset of clinical symptoms of AD such as the overproduction of AĂ and cerebral hypoperfusion
Expression et fonction des prĂ©sĂ©nilines vasculaires et exploration de lâhypothĂšse vasculaire de la Maladie dâAlzheimer
Les prĂ©sĂ©nilines PS1 et PS2 sont impliquĂ©es dans plusieurs fonctions cellulaires par lâintermĂ©diaire de leur activitĂ© protĂ©olytique ?-sĂ©crĂ©tase qui clive de nombreux substrats y compris la protĂ©ine prĂ©curseur amyloĂŻde (APP). Les mutations des prĂ©sĂ©nilines, Ă lâorigine des formes familiales de la maladie dâAlzheimer (MA), augmentent la production de peptides Ă-amyloĂŻde (AĂ) qui sâaccumulent dans le parenchyme cĂ©rĂ©bral et dans la paroi vasculaire, et affectent les signaux calciques de plusieurs types cellulaires. Le rĂ©seau vasculaire des patients atteints de la MA est affectĂ© structurellement et fonctionnellement bien avant que ne se dĂ©clarent les troubles cognitifs. De plus, les pathologies cardiovasculaires sont des facteurs de risque majeurs pour les formes sporadiques de la MA. Comme les bases molĂ©culaires de la vasculopathie liĂ©e Ă la MA ne sont pas Ă©tablies, nous avons choisi les prĂ©sĂ©nilines comme molĂ©cule cible dans le systĂšme vasculaire. Nous avons montrĂ© lâexpression des prĂ©sĂ©nilines et des protĂ©ines partenaires du complexe ?-sĂ©crĂ©tase, Nicastrine, Aph-1 et Pen-2 dans les vaisseaux cĂ©rĂ©braux et pĂ©riphĂ©riques. Lâensemble gĂ©nĂšre une activitĂ© ?-sĂ©crĂ©tase et la production de peptides AĂ pathogĂšnes dans les cellules musculaires lisses, soutenant lâhypothĂšse de lâorigine vasculaire dâAĂ dans la pathologie amyloĂŻde. De plus, les mutations de PS1 dĂ©rĂ©gulent la signalisation calcique intracellulaire des artĂšres cĂ©rĂ©brales, en augmentant lâactivitĂ© des canaux de libĂ©ration du Ca2+ activĂ©s par lâIP3 (IP3R) et la recapture du Ca2+ par les pompes du rĂ©ticulum sarco-endoplasmique Ca2+-ATPase (SERCA). La dĂ©rĂ©gulation de lâhomĂ©ostasie calcique par les prĂ©sĂ©nilines mutĂ©es pourrait avoir des consĂ©quences sur la rĂ©activitĂ© vasculaire des vaisseaux cĂ©rĂ©braux. En conclusion, nous avons mis en Ă©vidence lâimportance physiologique des prĂ©sĂ©nilines dans le rĂ©seau vasculaire et lâensemble de nos travaux permet de mieux comprendre comment les vaisseaux participent Ă lâapparition des symptĂŽmes cliniques de la MA que sont la surproduction dâAĂ et lâhypoperfusion cĂ©rĂ©brale.Presenilins PS1 and PS2 are involved in several cellular functions through their ?- secretase proteolytic activity, which cleaves many substrates including the amyloid precursor protein (APP). Mutations in presenilins genes are responsible for the majority of familial forms of Alzheimer's disease (AD). Presenilins mutations increased production of Ă-amyloid peptide (AĂ) that accumulates in the brain parenchyma and the vascular wall, and affect calcium signals in several cell types. The vasculature of patients with AD is structurally and functionally affected before cognitive impairment appearance. In addition, cardiovascular diseases are major risk factors for sporadic forms of AD. As the molecular basis of the vasculopathy associated with AD is not established, we chose presenilins as target molecule in the vascular system. We showed the expression of presenilin and protein partners of ?-secretase complex, nicastrin, Aph-1 and Pen-2 in cerebral and peripheral blood vessels. Vascular wall generate a ?-secretase activity and production of pathogenic AĂ peptides supporting the hypothesis of vascular origin of AĂ in amyloid pathology. Furthermore, PS1 mutations disturb intracellular calcium signalling in cerebral arteries by first increasing channel activity of Ca2+ release activated by IP3 (IP3R) and second increasing reuptake of Ca2+ by Sarco/Endoplasmic Reticulum Ca2+-ATPase pump (SERCA). Dysregulation of calcium homeostasis by the mutant presenilins might affect vascular reactivity of cerebral vessels. In conclusion, we demonstrated the physiological importance of presenilins in the vascular network and our studies provide new insight on how cerebral blood vessels are involved in the onset of clinical symptoms of AD such as the overproduction of AĂ and cerebral hypoperfusion
Revisiting enigmatic cortical calretinin-expressing interneurons
International audienceCortical calretinin (CR)-expressing interneurons represent a heterogeneous subpopulation of about 10â30% of GABAergic interneurons, which altogether total ca. 12â20% of all cortical neurons. In the rodent neocortex, CR cells display different somatodendritic morphologies ranging from bipolar to multipolar but the bipolar cells and their variations dominate. They are also diverse at the molecular level as they were shown to express numerous neuropeptides in different combinations including vasoactive intestinal polypeptide (VIP), cholecystokinin (CCK), neurokinin B (NKB) corticotrophin releasing factor (CRF), enkephalin (Enk) but also neuropeptide Y (NPY) and somatostatin (SOM) to a lesser extent. CR-expressing interneurons exhibit different firing behaviors such as adapting, bursting or irregular. They mainly originate from the caudal ganglionic eminence (CGE) but a subpopulation also derives from the dorsal part of the medial ganglionic eminence (MGE). Cortical GABAergic CR-expressing interneurons can be divided in two main populations: VIP-bipolar interneurons deriving from the CGE and SOM-Martinotti-like interneurons originating in the dorsal MGE. Although bipolar cells account for the majority of CR-expressing interneurons, the roles they play in cortical neuronal circuits and in the more general metabolic physiology of the brain remained elusive and enigmatic. The aim of this review is, firstly, to provide a comprehensive view of the morphological, molecular and electrophysiological features defining this cell type. We will, secondly, also summarize what is known about their place in the cortical circuit, their modulation by subcortical afferents and the functional roles they might play in neuronal processing and energy metabolism
Supragranular Pyramidal Cells Exhibit Early Metabolic Alterations in the 3xTg-AD Mouse Model of Alzheimerâs Disease
International audienceThe impairment of cerebral glucose utilization is an early and predictive biomarker of Alzheimer's disease (AD) that is likely to contribute to memory and cognition disorders during the progression of the pathology. Yet, the cellular and molecular mechanisms underlying these metabolic alterations remain poorly understood. Here we studied the glucose metabolism of supragranular pyramidal cells at an early presymptomatic developmental stage in non-transgenic (non-Tg) and 3xTg-AD mice, a mouse model of AD replicating numerous hallmarks of the disease. We performed both intracellular glucose imaging with a genetically encoded fluorescence resonance energy transfer (FRET)-based glucose biosensor and transcriptomic profiling of key molecular elements of glucose metabolism with single-cell multiplex RT-PCR (scRT-mPCR). We found that juvenile pyramidal cells exhibit active glycolysis and pentose phosphate pathway at rest that are respectively enhanced and impaired in 3xTg-AD mice without alteration of neuronal glucose uptake or transcriptional modification. Given the importance of glucose metabolism for neuronal survival, these early alterations could initiate or at least contribute to the later neuronal dysfunction of pyramidal cells in AD
Presenilin 1 mutation decreases both calcium and contractile responses in cerebral arteries
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Engineered Wnt ligands enable blood-brain barrier repair in neurological disorders
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Impairment of Glycolysis-Derived L-Serine Production in Astrocytes Contributes to Cognitive Deficits in Alzheimer's Disease
Impairment of Glycolysis-Derived l-Serine Production in Astrocytes Contributes to Cognitive Deficits in Alzheimerâs Disease
International audienceAlteration of brain aerobic glycolysis is often observed early in the course of Alzheimer's disease (AD). Whether and how such metabolic dysregulation contributes to both synaptic plasticity and behavioral deficits in AD is not known. Here, we show that the astrocytic l-serine biosynthesis pathway, which branches from glycolysis, is impaired in young AD mice and in AD patients. l-serine is the precursor of d-serine, a co-agonist of synaptic NMDA receptors (NMDARs) required for synaptic plasticity. Accordingly, AD mice display a lower occupancy of the NMDAR co-agonist site as well as synaptic and behavioral deficits. Similar deficits are observed following inactivation of the l-serine synthetic pathway in hippocampal astrocytes, supporting the key role of astrocytic l-serine. Supplementation with l-serine in the diet prevents both synaptic and behavioral deficits in AD mice. Our findings reveal that astrocytic glycolysis controls cognitive functions and suggest oral l-serine as a ready-to-use therapy for AD