CD44 overexpression by oligodendrocytes: A novel mouse model of inflammation‐independent demyelination and dysmyelination

Abstract

The CD44 transmembrane glycoprotein family has been implicated in cell-cell adhesion and cell signaling in response to components of the extracellular matrix but its role in the nervous system is not understood. CD44 proteins are elevated in Schwann cells and oligodendrocytes following nervous system insults, in inflammatory demyelinating lesions, and in tumors. Here, we tested the hypothesis that elevated CD44 expression influences Schwann cell and oligodendrocyte functions by generating transgenic mice that express CD44 under the control of the 2',3'-cyclic nucleotide-3'-phosphodiesterase (CNPase) promoter. These mice failed to develop peripheral nerve or CNS tumors. However, they did develop severe tremors that were associated with CNS dysmyelination and progressive demyelination. Loss of CNS myelin was not due to alterations in early oligodendrocyte precursor differentiation, proliferation, or survival. Myelination in the PNS appeared normal. In no instance was there any evidence of an inflammatory response that could account for the loss of CNS myelin. These findings suggest that CNPase-CD44 mice are a novel model for noninflammatory progressive demyelinating disease and support a potential role for CD44 proteins expressed by glial cells in promoting demyelination.

Neuroprotective Properties of Cannabigerol in Huntington's Disease: Studies in R6/2 Mice and 3-Nitropropionate-lesioned Mice

“…Sgk1 was induced in 3NP mice compared with control mice (2.7-fold induction) and was also significantly downregulated in 3NP mice treated with CBG (−1.41-fold repression). Although, in general, these results confirm that the molecular mechanisms underling HD physiopathology are quite different in 3NP and R6/2 murine models (see below), previous studies have confirmed the relation of these two genes with HD and other neuroinflammatory disorders [31,32].…”

Hyaluronan Anchored to Activated CD44 on Central Nervous System Vascular Endothelial Cells Promotes Lymphocyte Extravasation in Experimental Autoimmune Encephalomyelitis

“…MOG was combined with complete Freund's adjuvant containing heat-inactivated mycobacterium tuberculosis as previously described (26).…”

Hyaluronidase and Hyaluronan Oligosaccharides Promote Neurological Recovery after Intraventricular Hemorrhage

“…Cell culture experiments have demonstrated that HA blocks OPC maturation (Marret et al, 1994;Back et al, 2005), and studies in an adult rodent model have shown that HMW HA accumulation in chronic lesions of demyelination inhibits OPC maturation (Back et al, 2005). Intriguingly, mice engineered to overexpress CD44 also exhibit inflammation-independent demyelination (Tuohy et al, 2004). Moreover, our previous study showed that suppression of inflammation by COX2 inhibition or TNF␣ downregulation promotes myelination in this animal model (Vinukonda et al, 2010).…”

“…TLR2/4 receptors are activated in cerebral ischemia, trauma, hemorrhage, and infection (Konat et al, 2006;Fischer and Ehlers, 2008;Rivest, 2009), and inhibition of TLR2/4 offers neuroprotection in several adult rodent models of brain injury (Lehnardt et al, 2007;Tang et al, 2007). CD44 levels are chronically elevated in demyelinating lesions of multiple sclerosis, and antagonizing CD44 promotes remyelination and neurological recovery (Tuohy et al, 2004;Guan et al, 2011). Hence, specific fragments of HA can induce white matter injury, which can potentially be reversed by degrading HA or by blocking its binding receptors.…”

“…HA oligosaccharides of 8 -21 monosaccharides (ϳ1.5 kDa) have been used to remove the HCs from HC-HA complexes, thereby reducing the concentration of pathological HC-HA (Lauer et al, 2013b). HA oligosaccharides also impede HA-CD44 interaction by inducing CD44 receptor cleavage and by competitive binding to CD44 (Sugahara et al, 2003;Teriete et al, 2004). Indeed, HA oligosaccharide treatment offers neuroprotection in a mouse model of experimental allergic encephalitis .…”