Targeting demyelination via α-secretases promoting sAPPα release to enhance remyelination in central nervous system

Llufriu-Dabén, Gemma; Carrete, Alex; Chierto, Elena; Mailleux, Jo; Camand, Emeline; Simon, Anne; Vanmierlo, Tim; Rose, Christiane; Allinquant, Bernadette; Hendriks, Jerome J. A.; Massaad, Charbel; Meffre, Delphine; Jafarian-Tehrani, Mehrnaz

doi:10.1016/j.nbd.2017.09.008

Cited by 21 publications

(12 citation statements)

References 70 publications

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“…Other evidence supporting APP having a critical role in axon remyelination is obtained in reports showing high levels of APP immunoreactivity in premyelinating oligodendrocyte expressing cells and in demyelinating lesions (Ferguson et al, ; Gehrmann, Banati, Cuzner, Kreutzberg, & Newcombe, ). Moreover, a recent study demonstrated that the addition of sAPPα, the α‐secretase cleavage product, protected myelinated axons from demyelination while also promoting remyelination (Llufriu‐Daben et al, ). Taken together, these data make a strong case for having a major functional role in axon remyelination.…”

Section: Discussionmentioning

confidence: 99%

Amyloid precursor protein and amyloid precursor‐like protein 2 have distinct roles in modulating myelination, demyelination, and remyelination of axons

Truong

Ciccotosto

Merson

et al. 2018

Glia

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The identification of factors that regulate myelination provides important insight into the molecular mechanisms that coordinate nervous system development and myelin regeneration after injury. In this study, we investigated the role of amyloid precursor protein (APP) and its paralogue amyloid precursor‐like protein 2 (APLP2) in myelination using APP and APLP2 knockout (KO) mice. Given that BACE1 regulates myelination and myelin sheath thickness in both the peripheral and central nervous systems, we sought to determine if APP and APLP2, as alternate BACE1 substrates, also modulate myelination, and therefore provide a better understanding of the events regulating axonal myelination. In the peripheral nervous system, we identified that adult, but not juvenile KO mice, have lower densities of myelinated axons in their sciatic nerves while in the central nervous system, axons within both the optic nerves and corpus callosum of both KO mice were significantly hypomyelinated compared to wild‐type (WT) controls. Biochemical analysis demonstrated significant increases in BACE1 and myelin oligodendrocyte glycoprotein and decreased NRG1 and proteolipid protein levels in both KO brain tissue. The acute cuprizone model of demyelination/remyelination revealed that whereas axons in the corpus callosum of WT and APLP2‐KO mice underwent similar degrees of demyelination and subsequent remyelination, the myelinated callosal axons in APP‐KO mice were less susceptible to cuprizone‐induced demyelination and showed a failure in remyelination after cuprizone withdrawal. These data identified APP and APLP2 as modulators of normal myelination and demyelination/remyelination conditions. Deletion of APP and APLP2 identifies novel interplays between the BACE1 substrates in the regulation of myelination.

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Section: Discussionmentioning

confidence: 99%

Amyloid precursor protein and amyloid precursor‐like protein 2 have distinct roles in modulating myelination, demyelination, and remyelination of axons

Truong

Ciccotosto

Merson

et al. 2018

Glia

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“…It was shown that 35 proteins of the myelin proteome [21] were also identified by the plasma membrane enrichment approach. Both organotypic slice culture models with demyelinating lesions [24,25] and single topographic regions dissected from murine brains (corpus callosum, cerebellum, spinal cord [26,27]) are difficult to analyze due to their small sample volume and protein mass. However, by the use of our protocol presented in this study, these samples are now accessible for proteome-based investigation.…”

Section: Discussionmentioning

confidence: 99%

Membrane Protein Identification in Rodent Brain Tissue Samples and Acute Brain Slices

Joost

Mikkat

Wille

et al. 2019

Cells

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Acute brain slices are a sample format for electrophysiology, disease modeling, and organotypic cultures. Proteome analyses based on mass spectrometric measurements are seldom used on acute slices, although they offer high-content protein analyses and explorative approaches. In neuroscience, membrane proteins are of special interest for proteome-based analysis as they are necessary for metabolic, electrical, and signaling functions, including myelin maintenance and regeneration. A previously published protocol for the enrichment of plasma membrane proteins based on aqueous two-phase polymer systems followed by mass spectrometric protein identification was adjusted to the small sample size of single acute murine slices from newborn animals and the reproducibility of the results was analyzed. For this, plasma membrane proteins of 12 acute slice samples from six animals were enriched and analyzed by liquid chromatography-mass spectrometry. A total of 1161 proteins were identified, of which 369 were assigned to membranes. Protein abundances showed high reproducibility between samples. The plasma membrane protein separation protocol can be applied to single acute slices despite the low sample size and offers a high yield of identifiable proteins. This is not only the prerequisite for proteome analysis of organotypic slice cultures but also allows for the analysis of small-sized isolated brain regions at the proteome level.

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“…The number of APP aggregates was quantified per slice, for a total of 4–8 slices per condition from three independent experiments. The analysis of paranodal junctions was performed on slices co-immunostained with Caspr and MAG on images acquired for a total of 4–6 slices per condition from four independent experiments, as previously reported [63, 64].…”

Section: Methodsmentioning

confidence: 99%

Mechanical Stretch of High Magnitude Provokes Axonal Injury, Elongation of Paranodal Junctions, and Signaling Alterations in Oligodendrocytes

et al. 2018

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Increasing findings suggest that demyelination may play an important role in the pathophysiology of brain injury, but the exact mechanisms underlying such damage are not well known. Mechanical tensile strain of brain tissue occurs during traumatic brain injury. Several studies have investigated the cellular and molecular events following a static tensile strain of physiological magnitude on individual cells such as oligodendrocytes. However, the pathobiological impact of high-magnitude mechanical strain on oligodendrocytes and myelinated fibers remains under investigated. In this study, we reported that an applied mechanical tensile strain of 30% on mouse organotypic culture of cerebellar slices induced axonal injury and elongation of paranodal junctions, two hallmarks of brain trauma. It was also able to activate MAPK-ERK1/2 signaling, a stretch-induced responsive pathway. The same tensile strain applied to mouse oligodendrocytes in primary culture induced a profound damage to cell morphology, partial cell loss, and a decrease of myelin protein expression. The lower tensile strain of 20% also caused cell loss and the remaining oligodendrocytes appeared retracted with decreased myelin protein expression. Finally, high-magnitude tensile strain applied to 158N oligodendroglial cells altered myelin protein expression, dampened MAPK-ERK1/2 and MAPK-p38 signaling, and enhanced the production of reactive oxygen species. The latter was accompanied by increased protein oxidation and an alteration of anti-oxidant defense that was strain magnitude-dependent. In conclusion, mechanical stretch of high magnitude provokes axonal injury with significant alterations in oligodendrocyte biology that could initiate demyelination. Electronic supplementary material The online version of this article (10.1007/s12035-018-1372-6) contains supplementary material, which is available to authorized users.

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Targeting demyelination via α-secretases promoting sAPPα release to enhance remyelination in central nervous system

Cited by 21 publications

References 70 publications

Amyloid precursor protein and amyloid precursor‐like protein 2 have distinct roles in modulating myelination, demyelination, and remyelination of axons

Amyloid precursor protein and amyloid precursor‐like protein 2 have distinct roles in modulating myelination, demyelination, and remyelination of axons

Membrane Protein Identification in Rodent Brain Tissue Samples and Acute Brain Slices

Mechanical Stretch of High Magnitude Provokes Axonal Injury, Elongation of Paranodal Junctions, and Signaling Alterations in Oligodendrocytes

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