Publications by authors named "Alexis Bemelmans"

6 Publications

  • Page 1 of 1

Complex roles for reactive astrocytes in the triple transgenic mouse model of Alzheimer disease.

Neurobiol Aging 2020 06 18;90:135-146. Epub 2020 Feb 18.

Université Paris-Saclay, CEA, CNRS, MIRCen, Laboratoire des Maladies Neurodégénératives, Fontenay-aux-Roses, France. Electronic address:

In Alzheimer disease (AD), astrocytes undergo complex changes and become reactive. The consequences of this reaction are still unclear. To evaluate the net impact of reactive astrocytes in AD, we developed viral vectors targeting astrocytes that either activate or inhibit the Janus kinase-signal transducer and activator of transcription 3 (JAK2-STAT3) pathway, a central cascade controlling astrocyte reaction. We aimed to evaluate whether reactive astrocytes contribute to tau as well as amyloid pathologies in the hippocampus of 3xTg-AD mice, an AD model that develops tau hyper-phosphorylation and amyloid deposition. JAK2-STAT3 pathway-mediated modulation of reactive astrocytes in 25% of the hippocampus of 3xTg-AD mice did not significantly influence tau phosphorylation or amyloid processing and deposition at early, advanced, and terminal disease stage. Interestingly, inhibition of the JAK2-STAT3 pathway in hippocampal astrocytes did not improve spatial memory in the Y maze but it did reduce anxiety in the elevated plus maze. Our unique approach to specifically manipulate reactive astrocytes in situ show they may impact behavioral outcomes without influencing tau or amyloid pathology.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.02.010DOI Listing
June 2020

A proline-rich motif on VGLUT1 reduces synaptic vesicle super-pool and spontaneous release frequency.

Elife 2019 10 30;8. Epub 2019 Oct 30.

Interdisciplinary Institute for Neuroscience, Université de Bordeaux, Bordeaux, France.

Glutamate secretion at excitatory synapses is tightly regulated to allow for the precise tuning of synaptic strength. Vesicular Glutamate Transporters (VGLUT) accumulate glutamate into synaptic vesicles (SV) and thereby regulate quantal size. Further, the number of release sites and the release probability of SVs maybe regulated by the organization of active-zone proteins and SV clusters. In the present work, we uncover a mechanism mediating an increased SV clustering through the interaction of VGLUT1 second proline-rich domain, endophilinA1 and intersectin1. This strengthening of SV clusters results in a combined reduction of axonal SV super-pool size and miniature excitatory events frequency. Our findings support a model in which clustered vesicles are held together through multiple weak interactions between Src homology three and proline-rich domains of synaptic proteins. In mammals, VGLUT1 gained a proline-rich sequence that recruits endophilinA1 and turns the transporter into a regulator of SV organization and spontaneous release.
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http://dx.doi.org/10.7554/eLife.50401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6861006PMC
October 2019

Structural and functional connections between the median and the ventrolateral preoptic nucleus.

Brain Struct Funct 2019 Dec 6;224(9):3045-3057. Epub 2019 Sep 6.

Neuroglial Interactions in Cerebral Physiopathology, Center for Interdisciplinary Research in Biology, Centre National de la Recherche Scientifique UMR 7241, Institut National de la Santé et de la Recherche Médicale U1050, Collège de France, Labex Memolife, PSL-University, 11 place Marcelin Berthelot, 75005, Paris, France.

The median preoptic nucleus (MnPO) and the ventrolateral preoptic nucleus (VLPO) are two brain structures that contain neurons essential for promoting non-rapid eye movement (NREM) sleep. However, their connections are still largely unknown. Here, we describe for the first time a slice preparation with an oblique coronal slicing angle at 70° from the horizontal in which their connectivity is preserved. Using the in vivo iDISCO method following viral infection of the MnPO or ex vivo biocytin crystal deposition in the MnPO of mouse brain slices, we revealed a strong axonal pathway from the MnPO to the VLPO. Then, to further explore the functionality of these projections, acute 70° slices were placed on multielectrode arrays (MEAs) and electrical stimulations were performed near the MnPO. Recordings of the signals propagation throughout the slices revealed a preferential pathway from the MnPO to the VLPO. Finally, we performed an input-output curve of field responses evoked by stimulation of the MnPO and recorded in the VLPO. We found that field responses were inhibited by GABA receptor antagonist, suggesting that afferent inputs from the MnPO activate VLPO neuronal networks by disinhibition.
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http://dx.doi.org/10.1007/s00429-019-01935-4DOI Listing
December 2019

Fast calcium transients in dendritic spines driven by extreme statistics.

PLoS Biol 2019 06 4;17(6):e2006202. Epub 2019 Jun 4.

Computational Biology and Applied Mathematics, Institut de Biologie de l'École Normale Supérieure, Paris, France.

Fast calcium transients (<10 ms) remain difficult to analyse in cellular microdomains, yet they can modulate key cellular events such as trafficking, local ATP production by endoplasmic reticulum-mitochondria complex (ER-mitochondria complex), or spontaneous activity in astrocytes. In dendritic spines receiving synaptic inputs, we show here that in the presence of a spine apparatus (SA), which is an extension of the smooth ER, a calcium-induced calcium release (CICR) is triggered at the base of the spine by the fastest calcium ions arriving at a Ryanodyne receptor (RyR). The mechanism relies on the asymmetric distributions of RyRs and sarco/ER calcium-ATPase (SERCA) pumps that we predict using a computational model and further confirm experimentally in culture and slice hippocampal neurons. The present mechanism for which the statistics of the fastest particles arriving at a small target, followed by an amplification, is likely to be generic in molecular transduction across cellular microcompartments, such as thin neuronal processes, astrocytes, endfeets, or protrusions.
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http://dx.doi.org/10.1371/journal.pbio.2006202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6548358PMC
June 2019

Modulation of astrocyte reactivity improves functional deficits in mouse models of Alzheimer's disease.

Acta Neuropathol Commun 2018 10 16;6(1):104. Epub 2018 Oct 16.

Commissariat à l'Energie Atomique et aux Energies Alternatives, Département de la Recherche Fondamentale, Institut de Biologie François Jacob, Centre National de Recherche en Génomique Humaine (CNRGH), F-91057, Evry, France.

Astrocyte reactivity and neuroinflammation are hallmarks of CNS pathological conditions such as Alzheimer's disease. However, the specific role of reactive astrocytes is still debated. This controversy may stem from the fact that most strategies used to modulate astrocyte reactivity and explore its contribution to disease outcomes have only limited specificity. Moreover, reactive astrocytes are now emerging as heterogeneous cells and all types of astrocyte reactivity may not be controlled efficiently by such strategies.Here, we used cell type-specific approaches in vivo and identified the JAK2-STAT3 pathway, as necessary and sufficient for the induction and maintenance of astrocyte reactivity. Modulation of this cascade by viral gene transfer in mouse astrocytes efficiently controlled several morphological and molecular features of reactivity. Inhibition of this pathway in mouse models of Alzheimer's disease improved three key pathological hallmarks by reducing amyloid deposition, improving spatial learning and restoring synaptic deficits.In conclusion, the JAK2-STAT3 cascade operates as a master regulator of astrocyte reactivity in vivo. Its inhibition offers new therapeutic opportunities for Alzheimer's disease.
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http://dx.doi.org/10.1186/s40478-018-0606-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6190663PMC
October 2018

Loss of Otx2 in the adult retina disrupts retinal pigment epithelium function, causing photoreceptor degeneration.

J Neurosci 2013 Jun;33(24):9890-904

Institut de Biologie Valrose, University of Nice Sophia Antipolis, UFR Sciences, Nice F-06108, France.

Photoreceptors are specialized neurons of the retina that receive nursing from the adjacent retinal pigment epithelium (RPE). Frequent in the elderly, photoreceptor loss can originate from primary dysfunction of either cell type. Despite intense interest in the etiology of these diseases, early molecular actors of late-onset photoreceptor degeneration remain elusive, mostly because of the lack of dedicated models. Conditional Otx2 ablation in the adult mouse retina elicits photoreceptor degeneration, providing a new model of late-onset neuronal disease. Here, we use this model to identify the earliest events after Otx2 ablation. Electroretinography and gene expression analyses suggest a nonautonomous, RPE-dependent origin for photoreceptor degeneration. This is confirmed by RPE-specific ablation of Otx2, which results in similar photoreceptor degeneration. In contrast, constitutive Otx2 expression in RPE cells prevents degeneration of photoreceptors in Otx2-ablated retinas. We use chromatin immunoprecipitation followed by massive sequencing (ChIP-seq) analysis to identify the molecular network controlled in vivo by Otx2 in RPE cells. We uncover four RPE-specific functions coordinated by Otx2 that underpin the cognate photoreceptor degeneration. Many direct Otx2 target genes are associated with human retinopathies, emphasizing the significance of the model. Importantly, we report a secondary genetic response after Otx2 ablation, which largely precedes apoptosis of photoreceptors, involving inflammation and stress genes. These findings thus provide novel general markers for clinical detection and prevention of neuronal cell death.
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http://dx.doi.org/10.1523/JNEUROSCI.1099-13.2013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6618395PMC
June 2013
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