Abstract
Oligodendrocyte progenitor cell (OPC) differentiation is an important therapeutic target to promote remyelination in multiple sclerosis (MS). We previously reported hyperphosphorylated and aggregated microtubule‐associated protein tau in MS lesions, suggesting its involvement in axonal degeneration. However, the influence of pathological tau‐induced axonal damage on the potential for remyelination is unknown. Therefore, we investigated OPC differentiation in human P301S tau (P301S‐htau) transgenic mice, both in vitro and in vivo following focal demyelination. In 2‐month‐old P301S‐htau mice, which show hyperphosphorylated tau in neurons, we found atrophic axons in the spinal cord in the absence of prominent axonal degeneration. These signs of early axonal damage were associated with microgliosis and an upregulation of IL‐1β and TNFα. Following in vivo focal white matter demyelination we found that OPCs differentiated more efficiently in P301S‐htau mice than wild type (Wt) mice. We also found an increased level of myelin basic protein within the lesions, which however did not translate into increased remyelination due to higher susceptibility of P301S‐htau axons to demyelination‐induced degeneration compared to Wt axons. In vitro experiments confirmed higher differentiation capacity of OPCs from P301S‐htau mice compared with Wt mice‐derived OPCs. Because the OPCs from P301S‐htau mice do not ectopically express the transgene, and when isolated from newborn mice behave like Wt mice‐derived OPCs, we infer that their enhanced differentiation capacity must have been acquired through microenvironmental priming. Our data suggest the intriguing concept that damaged axons may signal to OPCs and promote their differentiation in the attempt at rescue by remyelination. GLIA 2016;64:457–471
Highlights
Remyelination is the most efficient regenerative process of the adult CNS and is vital for functional recovery in demyelinating diseases like multiple sclerosis (MS) (Franklin et al, 2012)
Similar microglial clustering is frequently found in early stages of MS white matter in the absence of demyelination, but associated with axonal injury identified as accumulation of amyloid precursor protein (APP) and non-phosphorylated neurofilament (Singh et al, 2013)
This increase of oligodendrocytes in P301S-htau mice compared with wild type (Wt) mice may have resulted from either an enhanced recruitment of Oligodendrocyte progenitor cell (OPC) within the first few days after the lesion or from a more efficient OPC differentiation
Summary
Remyelination is the most efficient regenerative process of the adult CNS and is vital for functional recovery in demyelinating diseases like multiple sclerosis (MS) (Franklin et al, 2012). Remyelination becomes less efficient in the later stage of MS in part due to a failure of OPC differentiation (Franklin and ffrench-Constant, 2008; Kuhlmann et al., 2008; Wolswijk, 1998). Failure of remyelination is a major contributor to the accumulation of axonal and neuronal degeneration that characterizes the progressive stage of the disease in which clinical deficits accumulate over time (Bjartmar et al, 2000; De Stefano et al, 2001). The axonal degeneration observed after toxin-induced demyelination in mice depleted of OPCs is prevented by the transplantation of exogenous OPCs that restore remyelination capacity (Irvine and Blakemore, 2008). Enhancing remyelination, and OPC differentiation, is an important therapeutic strategy to promote neuroprotection in the progressive stage
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