APP overexpression prevents neuropathic pain and motoneuron death after peripheral nerve injury in mice

Kotulska, Katarzyna; Larysz‐Brysz, Magdalena; LePecheur, Marie; Marcol, Wiesław; Lewin–Kowalik, Joanna; Paly, Evelyn; London, Jacqueline

doi:10.1016/j.brainresbull.2009.10.023

Cited by 11 publications

(10 citation statements)

References 33 publications

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“…APP is secreted into the medium by most cultured cells and can function as an autocrine factor to induce neurite extension through cell-surface binding [49]. Reportedly, APP overexpression in mice following peripheral nerve injury prevented neuropathic pain [50,51] and motoneuron death [50]. In addition, the β-site APP cleaving enzyme 1 (BACE1), a sole β-secretase generating APP, is crucial for axonal and Schwann cell remyelination of injured nerves [52], and the genetic deletion of BACE1 leads to increased nerve regeneration [53].…”

Section: Discussionmentioning

confidence: 99%

Enhanced Nerve Regeneration by Exosomes Secreted by Adipose-Derived Stem Cells with or without FK506 Stimulation

Rau

Kuo

et al. 2021

IJMS

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Exosomes secreted by adipose-derived stem cells (ADSC-exo) reportedly improve nerve regeneration after peripheral nerve injury. Herein, we investigated whether pretreatment of ADSCs with FK506, an immunosuppressive drug that enhances nerve regeneration, could secret exosomes (ADSC-F-exo) that further augment nerve regeneration. Designed exosomes were topically applied to injured nerve in a mouse model of sciatic nerve crush injury to assess the nerve regeneration efficacy. Outcomes were determined by histomorphometric analysis of semi-thin nerve sections stained with toluidine blue, mouse neurogenesis PCR array, and neurotrophin expression in distal nerve segments. Isobaric tags for relative and absolute quantitation (iTRAQ) were used to profile potential exosomal proteins facilitating nerve regeneration. We observed that locally applied ADSC-exo and ADSC-F-exo significantly enhanced nerve regeneration after nerve crush injury. Pretreatment of ADSCs with FK506 failed to produce exosomes possessing more potent molecules for enhanced nerve regeneration. Proteomic analysis revealed that of 192 exosomal proteins detected in both ADSC-exo and ADSC-F-exo, histone deacetylases (HDACs), amyloid-beta A4 protein (APP), and integrin beta-1 (ITGB1) might be involved in enhancing nerve regeneration.

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Section: Discussionmentioning

confidence: 99%

Enhanced Nerve Regeneration by Exosomes Secreted by Adipose-Derived Stem Cells with or without FK506 Stimulation

Rau

Kuo

et al. 2021

IJMS

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“…Thus, in the Drosophila head injury model, APP was shown to be up‐regulated up to 7 days after the impact [56] and this observation was confirmed in APP overexpressing mice which had more efficient sciatic nerve regeneration after injury due to better organisation of regenerating fibres. In these mice, APP was also shown to prevent neuropathic pain [57].…”

Section: App and Normal Brain Functionsmentioning

confidence: 99%

The amyloid precursor protein: A biochemical enigma in brain development, function and disease

2013

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a b s t r a c tFor 20 years the amyloid cascade hypothesis of Alzheimer disease (AD) has placed the amyloid-b peptide (Ab), formed from the amyloid precursor protein (APP), centre stage in the process of neurodegeneration. However, no new therapeutic agents have reached the clinic through exploitation of the hypothesis. The APP metabolites, including Ab, generated by its proteolytic processing, have distinct physiological functions. In particular, the cleaved intracellular domain of APP (AICD) regulates expression of several genes, including APP itself, the b-secretase BACE-1 and the Ab-degrading enzyme, neprilysin and this transcriptional regulation involves direct promoter binding of AICD. Of the three major splice isoforms of APP (APP 695 , APP 751 , APP 770 ), APP 695 is the predominant neuronal form, from which Ab and transcriptionally-active AICD are preferentially generated by selective processing through the amyloidogenic pathway. Despite intensive research, the normal functions of the APP isoforms remain an enigma. APP plays an important role in brain development, memory and synaptic plasticity and secreted forms of APP are neuroprotective. A fuller understanding of the physiological and pathological actions of APP and its metabolic and gene regulatory network could provide new therapeutic opportunities in neurodegeneration, including AD.

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“…Autotomy, self-mutilation of a denervated limb [ 5 , 6 , 7 , 8 ], is very common in animals after PNI (e.g., mice, rats, and rabbits), especially in rats after sciatic nerve transection, when the incidence of autotomy reaches as high as 40–80% [ 5 , 7 , 9 ]. This behavior is painful and affects animal behavioral outcomes.…”

Section: Introductionmentioning

confidence: 99%

“…This behavior is painful and affects animal behavioral outcomes. Most studies attribute autotomy behavior to the formation of neuromas [ 8 , 10 , 11 ]. However, autotomy can also be observed in crush injuries as well as cutting and re-suturing of the sciatic nerve in rats [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

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Macrophage Activation in the Dorsal Root Ganglion in Rats Developing Autotomy after Peripheral Nerve Injury

Zhou

et al. 2021

IJMS

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Autotomy, self-mutilation of a denervated limb, is common in animals after peripheral nerve injury (PNI) and is a reliable proxy for neuropathic pain in humans. Understanding the occurrence and treatment of autotomy remains challenging. The objective of this study was to investigate the occurrence of autotomy in nude and Wistar rats and evaluate the differences in macrophage activation and fiber sensitization contributing to the understanding of autotomy behavior. Autotomy in nude and Wistar rats was observed and evaluated 6 and 12 weeks after sciatic nerve repair surgery. The numbers of macrophages and the types of neurons in the dorsal root ganglion (DRG) between the two groups were compared by immunofluorescence studies. Immunostaining of T cells in the DRG was also assessed. Nude rats engaged in autotomy with less frequency than Wistar rats. Autotomy symptoms were also relatively less severe in nude rats. Immunofluorescence studies revealed increased macrophage accumulation and activation in the DRG of Wistar rats. The percentage of NF200+ neurons was higher at 6 and 12 weeks in Wistar rats compared to nude rats, but the percentage of CGRP+ neurons did not differ between two groups. Additionally, macrophages were concentrated around NF200-labeled A fibers. At 6 and 12 weeks following PNI, CD4+ T cells were not found in the DRG of the two groups. The accumulation and activation of macrophages in the DRG may account for the increased frequency and severity of autotomy in Wistar rats. Our results also suggest that A fiber neurons in the DRG play an important role in autotomy.

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APP overexpression prevents neuropathic pain and motoneuron death after peripheral nerve injury in mice

Cited by 11 publications

References 33 publications

Enhanced Nerve Regeneration by Exosomes Secreted by Adipose-Derived Stem Cells with or without FK506 Stimulation

Enhanced Nerve Regeneration by Exosomes Secreted by Adipose-Derived Stem Cells with or without FK506 Stimulation

The amyloid precursor protein: A biochemical enigma in brain development, function and disease

Macrophage Activation in the Dorsal Root Ganglion in Rats Developing Autotomy after Peripheral Nerve Injury

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