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

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, dramatically increased the number of neuroblasts observed at the lesion 14 days after injury. Those neuroblasts were able to differentiate into cholinergic and GABAergic neurons 28 days after injury. We conclude that ADAM17 is a putative target to develop new therapeutic tools for the treatment of traumatic brain injury.

A novel PKC activating molecule promotes neuroblast differentiation and delivery of newborn neurons in brain injuries

“…In summary, all this indicates that EOF2 facilitated migration of neuroblasts and that these neuroblasts differentiated into mature neurons. Similar results have been obtained upon reduction of TGFα release by ADAM17 inhibition 8 . Therefore, it is feasible that the capacity of EOF2 to favor neuregulin release over TGFα is promoting neurogenesis in injuries.…”

“…In general, sample size used in statistical analysis were n = 6 for in vivo experiments and n = 5-9 for in vitro experiments. Sample sizes were chosen based on a previous works related to this one 8,22,29,47 .…”

“…Previous results have identified neuroblasts migrating from the SVZ towards the site of injury through the corpus callosum. However, in the absence of treatments these neuroblasts never reached the injured site 8 . This indicated that signaling molecules that lead neuroblasts towards the injury, need to be released-as described in Comte et al 2011, for Galectin-3-to maintain motility from the SVZ to the olfactory bulb 39 .…”

“…Most of these studies show a neurogenic response of the DG and SVZ together with the absence of newly generated neuroblast within the perilesional area in control conditions. Interestingly, inhibiting ADAM17-mediated release of TGFα resulted in a neurogenic response within the perilesional area that produced a large number of new neurons 8 . In agreement with these studies, we show in here that injuries of control mice treated with vehicle showed none or a very small number of neuroblasts.…”

“…These regions also react to an injury activating NSC to produce neural progenitor cells (NPC), stimulating proliferation and differentiation of NPC into neuroblasts, and altering migration patterns of these neuroblasts to lead them towards the injured area [4][5][6] . However, only a very small number of newly born neurons reach the lesion [7][8][9] . This is a consequence of the release of inflammatory signals that create a gliogenic/non-neurogenic environment within the injured tissue 10 .…”