Specific inhibition of ADAM17/TACE promotes neurogenesis in the injured motor cortex

Cell Death & Disease
Noelia Geribaldi-DoldánCarmen Castro

Abstract

Brain injuries in the adult mammalian brain are accompanied by a fast neurogenic response inside neurogenic niches. However, this response does not contribute to the generation of new neurons within damaged tissues like the cerebral cortex, which are essentially non-neurogenic. This occurs because injuries create a hostile environment that favors gliogenesis. Overexpression and sequential activation of the ADAM17/TGFα/EGFR signaling cascade are crucial for the generation of this gliogenic/non-neurogenic environment. Here, we demonstrate that chronic local infusion of a general metalloprotease inhibitor in areas of traumatic cortical injury in adult mice moderately increased the number of neuroblasts around the lesion, by facilitating the survival of neuroblasts and undifferentiated progenitors, which had migrated to the perilesional area from the subventricular zone. Next, we generated a dominant-negative version of ADAM17 metalloprotease, consisting of a truncated protein containing only the pro-domain (ADAM17-Pro). Specific inhibition of ADAM17 activity by ADAM17-Pro overexpression increased the generation of new neurons in vitro. Local overexpression of ADAM17-Pro in injured cortex in vivo, mediated by lentiviral vectors, dr...Continue Reading

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Citations

Apr 14, 2020·Expert Opinion on Drug Discovery·Prashant R MurumkarMange Ram Yadav
Apr 10, 2019·Neural Regeneration Research·Samuel Dominguez-GarciaNoelia Geribaldi-Doldán
Dec 14, 2018·Frontiers in Cellular Neuroscience·Francisco García-BernalCarmen Castro
Apr 6, 2019·Frontiers in Cell and Developmental Biology·Noelia Geribaldi-DoldánCarmen Castro
Sep 22, 2020·Pharmacology & Therapeutics·Jason D Vadhan, Robert C Speth
Dec 19, 2020·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Samuel Domínguez-GarcíaCarmen Castro
Feb 14, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Matteo CalligarisSimone Dario Scilabra

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Datasets Mentioned

BETA
GM6001
GM6001-

Methods Mentioned

BETA
PCR
transfection
Fluorescence microscopy
Fluorescence
electrophoresis

Software Mentioned

ImageJ

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