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 présénilines vasculaires et exploration de l’hypothèse vasculaire de la Maladie d’Alzheimer

Les présénilines PS1 et PS2 sont impliquées dans plusieurs fonctions cellulaires par l’intermédiaire de leur activité protéolytique ?-sécrétase qui clive de nombreux substrats y compris la protéine précurseur amyloïde (APP). Les mutations des présénilines, à l’origine des formes familiales de la maladie d’Alzheimer (MA), augmentent la production de peptides ß-amyloïde (Aß) qui s’accumulent dans le parenchyme cérébral et dans la paroi vasculaire, et affectent les signaux calciques de plusieurs types cellulaires. Le réseau vasculaire des patients atteints de la MA est affecté structurellement et fonctionnellement bien avant que ne se déclarent les troubles cognitifs. De plus, les pathologies cardiovasculaires sont des facteurs de risque majeurs pour les formes sporadiques de la MA. Comme les bases moléculaires de la vasculopathie liée à la MA ne sont pas établies, nous avons choisi les présénilines comme molécule cible dans le système vasculaire. Nous avons montré l’expression des présénilines et des protéines partenaires du complexe ?-sécrétase, Nicastrine, Aph-1 et Pen-2 dans les vaisseaux cérébraux et périphériques. L’ensemble génère une activité ?-sécrétase et la production de peptides Aß pathogènes dans les cellules musculaires lisses, soutenant l’hypothèse de l’origine vasculaire d’Aß dans la pathologie amyloïde. De plus, les mutations de PS1 dérégulent la signalisation calcique intracellulaire des artères cérébrales, en augmentant l’activité des canaux de libération du Ca2+ activés par l’IP3 (IP3R) et la recapture du Ca2+ par les pompes du réticulum sarco-endoplasmique Ca2+-ATPase (SERCA). La dérégulation de l’homéostasie calcique par les présénilines mutées pourrait avoir des conséquences sur la réactivité vasculaire des vaisseaux cérébraux. En conclusion, nous avons mis en évidence l’importance physiologique des présénilines dans le réseau vasculaire et l’ensemble de nos travaux permet de mieux comprendre comment les vaisseaux participent à l’apparition des symptômes cliniques de la MA que sont la surproduction d’Aß et l’hypoperfusion cérébrale.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 ß-amyloid peptide (Aß) 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 Aß peptides supporting the hypothesis of vascular origin of Aß 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 Aß and cerebral hypoperfusion

Expression et fonction des présénilines vasculaires et exploration de l’hypothèse vasculaire de la Maladie d’Alzheimer

Les présénilines PS1 et PS2 sont impliquées dans plusieurs fonctions cellulaires par l’intermédiaire de leur activité protéolytique ?-sécrétase qui clive de nombreux substrats y compris la protéine précurseur amyloïde (APP). Les mutations des présénilines, à l’origine des formes familiales de la maladie d’Alzheimer (MA), augmentent la production de peptides ß-amyloïde (Aß) qui s’accumulent dans le parenchyme cérébral et dans la paroi vasculaire, et affectent les signaux calciques de plusieurs types cellulaires. Le réseau vasculaire des patients atteints de la MA est affecté structurellement et fonctionnellement bien avant que ne se déclarent les troubles cognitifs. De plus, les pathologies cardiovasculaires sont des facteurs de risque majeurs pour les formes sporadiques de la MA. Comme les bases moléculaires de la vasculopathie liée à la MA ne sont pas établies, nous avons choisi les présénilines comme molécule cible dans le système vasculaire. Nous avons montré l’expression des présénilines et des protéines partenaires du complexe ?-sécrétase, Nicastrine, Aph-1 et Pen-2 dans les vaisseaux cérébraux et périphériques. L’ensemble génère une activité ?-sécrétase et la production de peptides Aß pathogènes dans les cellules musculaires lisses, soutenant l’hypothèse de l’origine vasculaire d’Aß dans la pathologie amyloïde. De plus, les mutations de PS1 dérégulent la signalisation calcique intracellulaire des artères cérébrales, en augmentant l’activité des canaux de libération du Ca2+ activés par l’IP3 (IP3R) et la recapture du Ca2+ par les pompes du réticulum sarco-endoplasmique Ca2+-ATPase (SERCA). La dérégulation de l’homéostasie calcique par les présénilines mutées pourrait avoir des conséquences sur la réactivité vasculaire des vaisseaux cérébraux. En conclusion, nous avons mis en évidence l’importance physiologique des présénilines dans le réseau vasculaire et l’ensemble de nos travaux permet de mieux comprendre comment les vaisseaux participent à l’apparition des symptômes cliniques de la MA que sont la surproduction d’Aß et l’hypoperfusion cérébrale.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 ß-amyloid peptide (Aß) 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 Aß peptides supporting the hypothesis of vascular origin of Aß 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 Aß and cerebral hypoperfusion

Revisiting enigmatic cortical calretinin-expressing interneurons

International audienceCortical calretinin (CR)-expressing interneurons represent a heterogeneous subpopulation of about 10–30% of GABAergic interneurons, which altogether total ca. 12–20% 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 Alzheimer’s 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

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