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Nathalie MACREZ




39 publication(s) depuis Juin 1997:


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27/12/2019 | Sci Rep   IF 4
Deficit in hippocampal ripples does not preclude spatial memory formation in APP/PS1 mice.
Jura B, Macrez N, Meyrand P, Bem T

Abstract:
General theory of declarative memory formation posits a cortical-hippocampal dialog during which hippocampal ripple oscillations support information transfer and long-term consolidation of hippocampus dependent memories. Brain dementia, as Alzheimer disease (AD), is accompanied by memory loss and inability to form new memories. A large body of work has shown variety of mechanisms acting at cellular and molecular levels which can putatively play an important role in the impairment of memory formation. However, far less is known about changes occurring at the network-level activity patterns that support memory processing. Using freely moving APP/PS1 mice, a model of AD, we undertook a study to unravel the alterations of the activity of hippocampal and cortical circuits during generation of ripples in the transgenic and wild-type mice undergoing encoding and consolidation of spatial information. We report that APP/PS1 animals are able to consolidate spatial memory despite a major deficit of hippocampal ripples occurrence rate and learning dependent dynamics. We propose that these impairments may be compensated by an increase of the occurrence of cortical ripples and reorganization of cortical-hippocampal interaction.




08/03/2019 | Sci Rep   IF 4
ApoE-fragment/Abeta heteromers in the brain of patients with Alzheimer's disease.
Mouchard A, Boutonnet MC, Mazzocco C, Biendon N, Macrez N

Abstract:
Identification of endogenous pathological amyloid beta peptides (Abeta) forms in the brains of patients with Alzheimer's disease (AD) is still unclear. In healthy brain, Abeta can associate with Apolipoprotein E (ApoE) which is involved in its metabolism and clearance. In the brain of patients with AD, ApoE is cleaved and produces ApoE fragments. We studied the forms of Abeta and their interaction with the ApoE fragments in post-mortem brains from control and AD patients by western blots and co-immunoprecipitation. Three Abeta-containing peptides and three ApoE fragments were specifically found in the brain of AD patients. Co-immunoprecipitations showed that ApoE fragments and Abeta1-42 peptides are co-partners in heteromers of 18 and 16 kDa while ApoE-fragments and Abeta peptides of 12 kDa did not interact with each other. Formation of the 18 kDa ApoE-fragment/Abeta heteromers is specifically increased in ApoE4 carriers and is a strong brain marker of AD while 16 kDa ApoE-fragment/Abeta and Abeta 12 kDa correlate to memory deficit. These data show that in patients with AD, ApoE fragmentation generates peptides that trap Abeta in the brain. Inhibiting the fragmentation or targeting ApoE fragments could be exploited to define strategies to detect or reverse AD.




10/2017 | Neurobiol Aging   IF 4.3
Presenilin 1 mutation decreases both calcium and contractile responses in cerebral arteries.
Toussay X, Morel JL, Biendon N, Rotureau L, Legeron FP, Boutonnet MC, Cho YH, Macrez N

Abstract:
Mutations or upregulation in presenilin 1 (PS1) gene are found in familial early-onset Alzheimer's disease or sporadic late-onset Alzheimer's disease, respectively. PS1 has been essentially studied in neurons and its mutation was shown to alter intracellular calcium (Ca(2+)) signals. Here, we showed that PS1 is expressed in smooth muscle cells (SMCs) of mouse cerebral arteries, and we assessed the effects of the deletion of exon 9 of PS1 (PS1dE9) on Ca(2+) signals and contractile responses of vascular SMC. Agonist-induced contraction of cerebral vessels was significantly decreased in PS1dE9 both in vivo and ex vivo. Spontaneous activity of Ca(2+) sparks through ryanodine-sensitive channels (RyR) was unchanged, whereas the RyR-mediated Ca(2+)-release activated by caffeine was shorter in PS1dE9 SMC when compared with control. Moreover, PS1dE9 mutation decreased the caffeine-activated capacitive Ca(2+) entry, and inhibitors of SERCA pumps reversed the effects of PS1dE9 on Ca(2+) signals. PS1dE9 mutation also leads to the increased expression of SERCA3, phospholamban, and RyR3. These results show that PS1 plays a crucial role in the cerebrovascular system and the vascular reactivity is decreased through altered Ca(2+) signals in PS1dE9 mutant mice.




11/2015 | Cell Calcium   IF 4.9
TRPP2 modulates ryanodine- and inositol-1,4,5-trisphosphate receptors-dependent Ca2+ signals in opposite ways in cerebral arteries.
Abdi A, Mazzocco C, Legeron FP, Yvert B, Macrez N, Morel JL

Abstract:
TRPP2 is a cationic channel expressed in plasma membrane and in sarcoplasmic reticulum. In several cell lines, TRPP2 is described as a reticulum Ca(2+) leak channel but it also interacts with ryanodine and inositol 1,4,5-trisphosphate (InsP3) receptors to inhibit and increase the release of Ca(2+) stores, respectively. TRPP2 is known to be expressed in vascular smooth muscle cells, however its function in Ca(2+) signals remains poorly described in native cells, principally because the pharmacology is not developed. TRPP2 was expressed in cerebral arteries. Triptolide evoked Ca(2+) responses in a Ca(2+)-free solution as well as permeabilized arteries. This Ca(2+) signal was inhibited in presence of antisense oligonucleotide and siRNA directed against TRPP2 and antibody directed against the first loop of TRPP2. The partial inhibition of TRPP2 expression increased both the caffeine-evoked Ca(2+) responses and in vivo contraction. It also decreased the InsP3-evoked Ca(2+) responses. Finally, aging affected the regulations in which TRPP2 is engaged, whereas the triptolide-evoked Ca(2+) response was not modified. Taken together, our results have shown that TRPP2 is implicated in triptolide-induced Ca(2+) release from intracellular Ca(2+) stores. TRPP2 functionally interacts with both ryanodine and InsP3 receptors. These interactions were not similar in adult and old mice.




19/02/2015 | j alzheimers dis   IF 3.9
An Eighteen-Month Helicobacter Infection Does Not Induce Amyloid Plaques or Neuroinflammation in Brains of Wild Type C57BL/6J Mice.
Baudron CR, Chambonnier L, Buissionniere A, Giese A, Macrez N, Cho Y, Fenelon V, Blaszczyk L, Dubus P, Lehours P, Megraud F, Salles N, Varon C

Abstract:
There is increasing evidence to support the role of infectious agents in the progression of Alzheimer's disease (AD), especially Helicobacter pylori (H. pylori). The impact of Helicobacter infection on the brain of non-AD predisposed mice was studied. For that, C57BL/6J mice were infected by oral gavage with H. pylori SS1 (n = 6) and Helicobacter felis (H. felis) (n = 6) or not infected (n = 6) for evaluation of neuroinflammation (anti-GFAP and anti-iba1 immunohistochemistry) and amyloid-beta deposition (thioflavin-S stain and anti-Abeta immunohistochemistry). After 18-month of infection, H. pylori SS1 and H. felis infection induced a strong gastric inflammation compared to non-infected mice, but did not induce brain neuroinflammation or amyloid-beta deposition.




Abstract:
Microgravity induces a redistribution of blood volume. Consequently, astronauts' body pressure is modified so that the upright blood pressure gradient is abolished, thereby inducing a modification in cerebral blood pressure. This effect is mimicked in the hindlimb unloaded rat model. After a duration of 8 days of unloading, Ca2+ signals activated by depolarization and inositol-1,4,5-trisphosphate intracellular release were increased in cerebral arteries. In the presence of ryanodine and thapsigargin, the depolarization-induced Ca2+ signals remained increased in hindlimb suspended animals, indicating that Ca2+ influx and Ca2+-induced Ca2+ release mechanism were both increased. Spontaneous Ca2+ waves and localized Ca2+ events were also investigated. Increases in both amplitude and frequency of spontaneous Ca2+ waves were measured in hindlimb suspension conditions. After pharmacological segregation of Ca2+ sparks and Ca2+ sparklets, their kinetic parameters were characterized. Hindlimb suspension induced an increase in the frequencies of both Ca2+ localized events, suggesting an increase of excitability. Labeling with bodipy compounds suggested that voltage-dependent Ca2+ channels and ryanodine receptor expressions were increased. Finally, the expression of the ryanodine receptor subtype 1 (RyR1) was increased in hindlimb unloading conditions. Taken together, these results suggest that RyR1 expression and voltage-dependent Ca2+ channels activity are the focal points of the regulation of Ca2+ signals activated by vasoconstriction in rat cerebral arteries with an increase of the voltage-dependent Ca2+ influx.




Abstract:
Gravity has a structural role for living systems. Tissue development, architecture, and organization are modified when the gravity vector is changed. In particular, microgravity induces a redistribution of blood volume and thus pressure in the astronaut body, abolishing an upright blood pressure gradient, inducing orthostatic hypotension. The present study was designed to investigate whether isolated vascular smooth muscle cells are directly sensitive to altered gravitational forces and, second, whether sustained blood pressure changes act on the same molecular target. Exposure to microgravity during 8 days in the International Space Station induced the decrease of ryanodine receptor subtype 1 expression in primary cultured myocytes from rat hepatic portal vein. Identical results were found in portal vein from mice exposed to microgravity during an 8-day shuttle spaceflight. To evaluate the functional consequences of this physiological adaptation, we have compared evoked calcium signals obtained in myocytes from hindlimb unloaded rats, in which the shift of blood pressure mimics the one produced by the microgravity, with those obtained in myocytes from rats injected with antisense oligonucleotide directed against ryanodine receptor subtype 1. In both conditions, calcium signals implicating calcium-induced calcium release were significantly decreased. In contrast, in spontaneous hypertensive rat, an increase in ryanodine receptor subtype 1 expression was observed as well as the calcium-induced calcium release mechanism. Taken together, our results shown that myocytes were directly sensitive to gravity level and that they adapt their calcium signaling pathways to pressure by the regulation of the ryanodine receptor subtype 1 expression.




01/2012 | Neurobiol Aging   IF 4.3
Early temporal short-term memory deficits in double transgenic APP/PS1 mice.
Lagadec S, Rotureau L, Hemar A, Macrez N, Delcasso S, Jeantet Y, Cho YH

Abstract:
We tested single APP (Tg2576) transgenic, PS1 (PS1dE9) transgenic, and double APP/PS1 transgenic mice at 3 and 6 months of age on the acquisition of a hippocampal-dependent operant 'differential reinforcement of low rate schedule' (DRL) paradigm. In this task mice are required to wait for at least 10 seconds (DRL-10s) between 2 consecutive nose poke responses. Our data showed that while single APP and PS1 transgene expression did not affect DRL learning and performance, mice expressing double APP/PS1 transgenes were impaired in the acquisition of DRL-10s at 6 months, but not at 3 months of age. The same impaired double transgenic mice, however, were perfectly capable of normal acquisition of signaled DRL-10s (SDRL-10s) task, a hippocampal-independent task, wherein mice were required to emit responses when the end of the 10-second delay was signaled by a lighting of the chamber. The age-dependent and early deficits of APP/PS1 mice suggest that the appetitive DRL paradigm is sensitive to the amyloid pathology present in double APP/PS1 mice, and that this mouse line represents a good model with which to study the efficacy of therapeutic strategies against Alzheimer's disease.




25/02/2010 | Eur J Pharmacol   IF 3.3
Comparison between gentamycin and exon skipping treatments to restore ryanodine receptor subtype 2 functions in mdx mouse duodenum myocytes.
Dabertrand F, Mironneau J, Henaff M, Macrez N, Morel JL

Abstract:
In Duchenne muscular dystrophy, a stop-codon mutation in the dystrophin gene induces an impairment of skeletal and smooth muscles contraction. In duodenum from mdx mouse, the disease model, the decrease of contractility was linked with the decrease of calcium signals encoded by ryanodine receptor subtype 2. Aminoglycoside and antisense oligonucleotide strategies were investigated to restore calcium signalling in the mdx mouse. Mdx mice were treated by intraperitoneal injection of gentamycin or 2-O-methyl antisense ribonucleotide directed against exon 23 of dystrophin for 2 weeks. The efficiency of both therapeutic strategies was determined by the level of dystrophin protein expression. The physiological effects of both treatments on ryanodine receptor expression and function were followed by RT-PCR, western blot and calcium measurements. Fourteen days after injection of gentamycin or anti-dystrophin antisense, the expression of dystrophin was recovered in skeletal muscle from treated mdx mice. In duodenum cells, RT-PCR and western blot indicated that the expression of ryanodine receptor subtype 2 was similar in treated mice than in control mice in association with the recovery of caffeine-induced Ca(2+) response. No significant difference was observed in the ryanodine subtype 3-dependent spontaneous Ca(2+) oscillations in untreated and treated mice. Conclusions - these results may help to explain the efficiency of aminoglycoside and anti-dystrophin antisense treatments in smooth muscle. Both treatments could be an interesting therapeutic option to restore smooth muscle contraction in patients with Duchenne muscular dystrophy.




09/2009 | j cell mol med
The decrease of expression of ryanodine receptor sub-type 2 is reversed by gentamycin sulphate in vascular myocytes from mdx mice.
Morel JL, Dabertrand F, Fritz N, Henaff M, Mironneau J, Macrez N

Abstract:
The mdx mouse, a model of the human Duchenne muscular dystrophy, displays impaired contractile function in skeletal, cardiac and smooth muscles. We explored the possibility that ryanodine receptor (RYR) expression could be altered in vascular muscle. The three RYR sub-types were expressed in portal vein myocytes. As observed through mRNA and protein levels, RYR2 expression was strongly decreased in mdx myocytes, whereas RYR3 and RYR1 expression were unaltered. The use of antisense oligonucleotide directed against RYR sub-types indicated that caffeine-induced Ca(2+) response and Ca(2+) spark frequency depended on RYR2 and RYR1. In mdx mice, caffeine-induced Ca(2+) responses were decreased in both amplitude and maximal rate of rise, and the frequency of Ca(2+) sparks was also strongly decreased. The gentamycin treatment was able to increase both the expression of RYR2 and the caffeine-induced Ca(2+) response to the same level as that observed in wild-type mice. Taken together, these results confirm that both RYR1 and RYR2 are required for vascular Ca(2+) signalling and indicate that inhibition of RYR2 expression may account for the decreased Ca(2+) release from the SR in mdx vascular myocytes. Finally, we suggest that gentamycin can restore the Ca(2+) signalling in smooth muscle from mdx mice by increasing RYR2 and dystrophin expression. These results may help explain the reduced efficacy of contraction in vascular myocytes of mdx mice and Duchenne muscular dystrophy-afflicted patients. Gentamycin treatment could be a good therapeutic tool to restore the vascular function.