Nogo receptor blockade overcomes remyelination failure after white matter stroke and stimulates functional recovery in aged mice

Abstract

White matter stroke is a distinct stroke subtype, accounting for up to 25% of stroke and constituting the second leading cause of dementia. The biology of possible tissue repair after white matter stroke has not been determined. In a mouse stroke model, white matter ischemia causes focal damage and adjacent areas of axonal myelin disruption and gliosis. In these areas of only partial damage, local white matter progenitors respond to injury, as oligodendrocyte progenitors (OPCs) proliferate. However, OPCs fail to mature into oligodendrocytes (OLs) even in regions of demyelination with intact axons and instead divert into an astrocytic fate. Local axonal sprouting occurs, producing an increase in unmyelinated fibers in the corpus callosum. The OPC maturation block after white matter stroke is in part mediated via Nogo receptor 1 (NgR1) signaling. In both aged and young adult mice, stroke induces NgR1 ligands and down-regulates NgR1 inhibitors during the peak OPC maturation block. Nogo ligands are also induced adjacent to human white matter stroke in humans. A Nogo signaling blockade with an NgR1 antagonist administered after stroke reduces the OPC astrocytic transformation and improves poststroke oligodendrogenesis in mice. Notably, increased white matter repair in aged mice is translated into significant poststroke motor recovery, even when NgR1 blockade is provided during the chronic time points of injury. These data provide a perspective on the role of NgR1 ligand function in OPC fate in the context of a specific and common type of stroke and show that it is amenable to systemic intervention to promote recovery.repair | oligodendrocyte progenitor cell | oligodendrocyte | subventricular zone | astrocyte I schemic stroke in the adult brain occurs in two basic forms. Occlusion of large brain arteries produces stroke that spans brain areas, including gray matter (cortex, striatum) and white matter regions. Stroke in small brain vessels often occurs only in subcortical white matter regions, and these infarcts account for up to 25% of all stroke. The incidence of white matter stroke is age-associated and is the second leading cause of dementia (1-3). The resulting infarcts are distinct from large artery stroke, not only in cause and location but also in progressive accumulation over time (1,3,4). Ischemic regions after white matter stroke grow, with progression of the damage even in the controlled conditions of a clinical trial (5). Importantly, the presence of white matter ischemic lesions closely correlates with abnormalities in cognition, balance, and gait and carries an increased risk of death (6, 7).Despite such clinical importance, white matter repair after white matter stroke is still relatively unknown, which is in part because most basic science studies of stroke focus on large artery infarcts, such as middle cerebral artery occlusions. Most of what is known about white matter repair is derived from studies in inflammatory or toxic injuries of white matter, such as multiple sclerosis (MS). In these nonstroke...

Gpr17, a Player in Lysolecithin-Induced Demyelination, Oligodendrocyte Survival, and Differentiation

“…Gpr17 was previously found to be expressed in OPCs and premature oligodendrocytes (Fumagalli et al, 2011), and it has been proposed to have a role in OPC differentiation and developmental myelination (Chen et al, 2009;Simon et al, 2016;Viganò et al, 2016). These studies showed that Gpr17 inhibits OPC differentiation in vitro and delays myelination during development in vivo.…”

“…A first step toward developing potential promyelinating therapies is to identify genes whose expression is affected during demyelination and subsequent remyelination. Ou et al (2016) used this approach and reported their findings in a study recently published in The Journal of Neuroscience.…”

“…Lysolecithin-treated oligodendrocytes showed numerous transcriptional alterations, including upregulation of Olig2. Because Olig2 is an important transcription factor for oligodendrocyte lineage cells (Lu et al, 2000;Zhou et al, 2000), Ou et al (2016) focused on this molecule and its potential downstream targets in subsequent experiments.…”

“…Thus, Gpr17 has received the nickname "damage sensor." The role of Gpr17 in remyelination has never been assessed, but given its role in CNS insult, Ou et al (2016) hypothesized that it is involved in lysolecithin-induced gliotoxicity.…”

“…First, they examined genes involved in apoptosis. It has been shown before that Gpr17 mediates its downstream signaling through the Gi ␣ subunit (G␣i), which inhibits cAMP production and, subsequently, the activity of protein kinase A (PKA) (Simon et al, 2016). Examining expression of different proapoptotic genes in Gpr17-deficient mice revealed that lysolecithin-induced upregulation of Gpr17 mediated PKA inhibition, which led to an upregulation of Xaf1 gene.…”