Rejuvenation of Regeneration in the Aging Central Nervous System

Ruckh, Julia M.; Zhao, J. W.; Shadrach, Jennifer L.; Wijngaarden, Peter van; Rao, Tata Nageswara; Wagers, Amy J.; Franklin, Robin J.M.

doi:10.1016/j.stem.2011.11.019

Cited by 573 publications

(589 citation statements)

References 30 publications

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“…The finding that older placebo‐treated participants experienced worse VEP latency recovery is consistent with the biological concept that spontaneous remyelination is negatively affected by aging 17, 18, 19, 20, 21. That the strongest opicinumab treatment effect was observed in this subgroup, suggests that LINGO‐1 blockade may be more effective in individuals whose initial clinical episode of CNS demyelination occurs at an older age.…”

Section: Discussionsupporting

confidence: 81%

“…First, younger participants may have greater inherent recovery potential and spontaneous remyelination, which may dampen any therapeutic effect of opicinumab; conversely, intrinsic remyelination may be weaker in older participants, with a greater margin for therapeutic enhancement in this subgroup 21. Second, younger participants may be less responsive to opicinumab because increased LINGO‐1 expression may not play a role in the lack of spontaneous remyelination.…”

Section: Discussionmentioning

confidence: 99%

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Predictors of response to opicinumab in acute optic neuritis

Cadavid

Balcer

Galetta

et al. 2018

Ann Clin Transl Neurol

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ObjectiveThe objective of this study was to evaluate prespecified and post hoc analyses in RENEW subgroups to identify participants more likely to benefit from opicinumab.Methods RENEW assessed the efficacy/safety of opicinumab versus placebo in participants with a first unilateral acute optic neuritis (AON) episode. Difference in visual evoked potential (VEP) latency of the affected eye at 24 weeks versus the fellow eye at baseline was the primary endpoint. Interactions between the primary endpoint and prespecified baseline variables (including age, timing of treatment initiation, and visual impairment) using the median as cut‐off were evaluated in the per protocol population using analysis of covariance (ANCOVA); subgroups based on preexisting brain T2 lesion volume were also analyzed. Interactions between the primary endpoint and retinal ganglion cell layer/inner plexiform layer (RGCL/IPL) and retinal nerve fiber layer (RNFL) thickness were assessed post hoc as was weight gain by treatment.ResultsTreatment benefit of opicinumab (n = 33) over placebo (n = 36) on the primary endpoint was greatest in participants older than the median age at baseline (≥33 years); the difference versus placebo for baseline age ≥33 years was −14.17 msec [P = 0.01] versus −0.89 msec for baseline age <33 years, [P = 0.87]). Post hoc analysis showed that VEP latency recovery was significantly associated with less RGCL/IPL thinning (P = 0.0164), occurring early on.InterpretationAge was the strongest prespecified baseline characteristic associated with a treatment effect of opicinumab. A strong association between VEP latency recovery at week 24 and early RGCL/IPL preservation was observed.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Predictors of response to opicinumab in acute optic neuritis

Cadavid

Balcer

Galetta

et al. 2018

Ann Clin Transl Neurol

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“…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 APP and non‐phosphorylated neurofilament (Singh et al, 2013). To note, an inflammatory microenvironment is essential for an efficient remyelination, for example for the removal of myelin debris from the demyelinated lesions (Kotter et al, 2005; Miron et al, 2013; Ruckh et al, 2012). Importantly, the cytokines IL‐1β and TNFα, which are upregulated in young P301S‐htau mice compared with Wt mice (Fig.…”

Section: Discussionmentioning

confidence: 99%

Neuronal expression of pathological tau accelerates oligodendrocyte progenitor cell differentiation

Ossola

Zhao

Compston

et al. 2015

Glia

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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

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“…Comparing mononuclear phagocytes between young and old mice, aged macrophages, and microglia exhibited reduced motility in response to laser-induced injury and extracellular ATP [197]. In demyelinating models, reduced migration of mononuclear cells [198], and impaired clearance of myelin debris in macrophages accompanied by an age-associated delay in remyelination have been observed [199][200][201]. Additionally, microglia isolated from aged mice displayed a reduced capability to engulf Aβ compared with young mice [202,203].…”

Section: Agingmentioning

confidence: 97%

Microglia and Monocyte-Derived Macrophages in Stroke

2016

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Historically, the brain has been considered an immune-privileged organ separated from the peripheral immune system by the blood-brain barrier. However, immune responses do occur in the brain in neurological conditions in which the integrity of the blood-brain barrier is compromised, exposing the brain to peripheral antigens and endogenous danger signals. While most of the associated pathological processes occur in the central nervous system, it is now clear that peripheral immune cells, especially mononuclear phagocytes, that infiltrate into the injury site play a key role in modulating the progression of primary brain injury development. As inflammation is a necessary and critical component for the subsequent injury resolution process, understanding the contribution of mononuclear phagocytes on the regulation of inflammatory responses may provide novel approaches for potential therapies. Furthermore, predisposed comorbid conditions at the time of stroke cause the alteration of stroke-induced immune and inflammatory responses and subsequently influence stroke outcome. In this review, we summarize a role for microglia and monocytes/macrophages in acute ischemic stroke in the context of normal and metabolically compromised conditions.

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Rejuvenation of Regeneration in the Aging Central Nervous System

Cited by 573 publications

References 30 publications

Predictors of response to opicinumab in acute optic neuritis

Predictors of response to opicinumab in acute optic neuritis

Neuronal expression of pathological tau accelerates oligodendrocyte progenitor cell differentiation

Microglia and Monocyte-Derived Macrophages in Stroke

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