Differences in the early inflammatory responses to toxin-induced demyelination are associated with the age-related decline in CNS remyelination
Abstract
CNS remyelination occurs more rapidly in young adult rats than in old rats. Since the inflammatory response initiated by demyelination is an important trigger for remyelination, we address whether ageing changes in remyelination are associated with changes in the inflammatory response. Using a toxin model of demyelination, where the inflammatory response largely comprises macrophages, we show that there is a delay in both recruitment and activation of OX-42+ and macrophage scavenger receptor B+ macrophages following demyelination in older rats (10-13 months) compared to young rats (8-10 weeks). This difference is associated with a slower onset of increased expression of several chemokine mRNAs. However, many inflammatory cytokines have similar mRNA expression patterns, with the exception of IL-1beta, IL-6 and TNF-alpha, which have prolonged expression in the older animals. Differences in IL-1beta mRNA expression, a cytokine specifically implicated in CNS remyelination, are not reflected in differences in protein expression detected by immunocytochemistry. These data relate the age-associated delay in remyelination efficiency to changes in the macrophage and inflammatory mediator response to demyelination.
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White matter demyelination injury provokes a reduced macrophage response in older rodents compared to younger controls.
“however, white matter demyelination injury provokes a reduced macrophage response in older rodents compared to younger controls (102).”
From The Inflammatory Continuum of Traumatic Brain Injury and Alzheimer’s Disease (2018) · cites this paper as [102]
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A silver lining of neuroinflammation: Beneficial effects on myelination
Goldstein, E. Z., Church, J. S., Hesp, Z. C., Popovich, P. G., & McTigue, D. M. (2016) · Experimental Neurology · doi:10.1016/j.expneurol.2016.05.001 · Cited by 38 · see citing works
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“To create an environment that permits remyelination, endogenous microglia and infiltrating macrophages must clear myelin debris remaining from the disintegrated sheath (12), and also secrete proregenerative factors (10, 11, 13).”
Self-citationThe need to incorporate aged animals into the preclinical modeling of neurological conditions
Sun, M., McDonald, S. J., Brady, R. D., Collins‐Praino, L. E., Yamakawa, G. R., Monif, M., O'Brien, T. J., CLOUD, G. C., Sobey, C. G., Mychasiuk, R., et al. (2019) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2019.12.027 · Cited by 43 · see citing works
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“Coincidentally, mRNA levels of TIMP1, a natural inhibitor of MMPs, were substantially increased at demyelination, and decreased at remyelination (14 DPL) compared with 5 DPL (Figure 1a).”
BackgroundMethodInfluentialSelf-citationThe remyelination Philosopher's Stone: stem and progenitor cell therapies for multiple sclerosis
Jadasz, J. J., Aigner, L., Rivera, F. J., & Küry, P. (2012) · Cell and Tissue Research · doi:10.1007/s00441-012-1331-x · Cited by 36 · see citing works
“Chemokines are of particular interest, since they have been shown to affect the differentiation and migration of NSPCs and of OPCs (Carbajal et al. 2010; Göttle et al. 2010; Patel et al. 2010).”
Backgroundde Jong, C. G. H. M., Gabius, H., & Baron, W. (2019) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03327-7 · Cited by 43 · see citing works
The influence of immunological stressors on traumatic brain injury
Sun, M., McDonald, S. J., Brady, R. D., O'Brien, T. J., & Shultz, S. R. (2018) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2018.01.007 · Cited by 41 · see citing works
“Similarly, pre-clinical studies have found that aged macrophages/monocytes also have impaired phagocytosis and chemotaxis (Zhao et al., 2006; Ruckh et al., 2012; Natrajan et al., 2015).”
Differentiation of mouse bone marrow derived stem cells toward microglia-like cells
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“In vitro, proliferating rat microglia have been reported to undergo telomere shortening [23] and aged microglia of several species have been observed to loose their ability to perform normal microglia functions [19,20,24-28].”
BackgroundToxin-Based Models to Investigate Demyelination and Remyelination
McMurran, C. E., Zhao, C., & Franklin, R. J. M. (2019) · Methods in molecular biology · doi:10.1007/978-1-4939-9072-6_21 · Cited by 45 · see citing works
“In contrast to live cells, RNA and protein from a small region of CNS containing a lysolecithin lesion have been reliably used to investigate remyelination [82, 83].”
BackgroundSelf-citationMicroglia: Senescence Impairs Clearance of Myelin Debris
Thériault, P., & Rivest, S. (2016) · Current Biology · doi:10.1016/j.cub.2016.06.066 · Cited by 34 · see citing works
Myelin Repair: From Animal Models to Humans
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Pioglitazone regulates myelin phagocytosis and multiple sclerosis monocytes
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Self-citationRemyelination After Cuprizone-Induced Demyelination Is Accelerated in Juvenile Mice
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“Hence, rapid clearance of myelin debris by activated microglia enhances the process of remyelination (26, 28, 55, 56).”
Tracking the evolution of CNS remyelinating lesion in mice with neutral red dye
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“Following demyelinating injury, the lesion site undergoes metabolic changes that influence cell reprogramming and differentiation, leading to oligodendrocyte maturation and myelin production (45, 46).”
BackgroundWelliver, R., Polanco, J. J., Seidman, R. A., Sinha, A. K., O'Bara, M. A., Khaku, Z. M., Santiago-González, D. S., Nishiyama, A., Wess, J., Feltri, M., et al. (2018) · Journal of Neuroscience · doi:10.1523/jneurosci.1862-17.2018 · Cited by 34 · see citing works
“Focal demyelination of the young adult (8- to 11-week-old) mouse spinal cord was induced as previously described (Zhao et al., 2006).”
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“Immune cells are responsible for the clearance of myelin debris, which contains proteins that inhibit OPC differentiation (Baer et al., 2009; Kotter et al., 2006; Rosenberg et al., 2008; Ruckh et al., 2012; Syed et al., 2008; Zhao et al., 2006).”
BackgroundBlommaert, J., Schroyen, G., Vandenbulcke, M., Radwan, A., Smeets, A., Peeters, R. R., Sleurs, C., Neven, P., Wildiers, H. P. M. W., Amant, F. C., et al. (2019) · Human Brain Mapping · doi:10.1002/hbm.24753 · Cited by 40 · see citing works
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“The literature considers rats as old at 10 months of age [33,34].”
BackgroundApproaches to Remyelination Therapies in Multiple Sclerosis
Wooliscroft, L., Silbermann, E., Cameron, M. H., & BOURDETTE, D. N. (2019) · Current Treatment Options in Neurology · doi:10.1007/s11940-019-0574-1 · Cited by 35 · see citing works
Paired Related Homeobox Protein 1 Regulates Quiescence in Human Oligodendrocyte Progenitors
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“Moreover, the agedependent decrease in remyelination is attributed equally to the intrinsic properties of aging OPCs [23] and the impaired response of aging microglia and macrophages to demyelination [24,25].”
BackgroundImpaired regeneration in aged nerves: Clearing out the old to make way for the new
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Nutritional factors and aging in demyelinating diseases
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“It is also important to consider the age-related modifications of the innate immune and growth factor responses to the demyelination process which interfere with myelin repair (Hinks and Franklin 2000; Zhao et al. 2006).”
BackgroundBeyond Clotting: A Role of Platelets in CNS Repair?
Rivera, F. J., Kazanis, I., Ghevaert, C., & Aigner, L. (2016) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2015.00511 · Cited by 26 · see citing works
“…a potent inhibitor of OPC differentiation (Kotter et al., 2006; Baer et al., 2009)] through phagocytosis, and (ii) they secrete cytokines, growth- and neurotrophic factors that stimulate OPC responses to demyelination (Setzu et al., 2006; Zhao et al., 2006; Ruckh et al., 2012; Miron et al., 2013).”
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Neuronal expression of pathological tau accelerates oligodendrocyte progenitor cell differentiation
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“Alkaline toluidine blue dye (0.5% Toluidine Blue1 0.5% Borax) (Sigma–Aldrich) was applied on semi-thin (1 lm) sections and heated with a Bunsen flame for 10 sec before washing with tap water (Zhao et al., 2006).”
InfluentialSelf-citationTan, G. A., Furber, K. L., Thangaraj, M. P., Sobchishin, L., Doucette, J. R., & Nazarali, A. J. (2017) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-017-0529-6 · Cited by 28 · see citing works
“There are also differences in microglia cell populations between the young and aging CNS (Grabert et al. 2016; Vela et al. 1995; Zhao et al. 2006), which are responsible for myelin debris clearance and promoting an environment conducive to neural repair.”
- Authors
- Zhao, C., Li, W.-W., & Franklin, R. J. M.
- Affiliations
- University of Cambridge (GB)
- Corresponding author
- Franklin, Robin J.M.
- Venue
- Neurobiology of Aging
- Publisher
- Elsevier BV
- Published
- 2006-09
- Volume
- 27
- Issue
- 9
- Pages
- 1298-1307
- ISSN
- 0197-4580 (ISSN-L)
- OpenAlex
- W2158151457
- Cited by
- 142
- References
- 45
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 2 · 2023: 3 · 2022: 5 · 2021: 7 · 2020: 8 · 2019: 16 · 2018: 10 · 2017: 11 · 2016: 10 · 2015: 10 · 2014: 8 · 2013: 8 · 2012: 4
- FWCI
- 3.79
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neurobiology of Aging (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust
- Multiple Sclerosis Society
- European Commission
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- demyelination, aging, neuroinflammation, macrophages, OX-42, chemokines, inflammatory cytokines, IL-1β, interleukin-6, TNF-α, myelin oligodendrocyte glycoprotein, age-related decline
- MeSH terms
- Aging, Animals, Cell Count, Central Nervous System, Demyelinating Diseases, Disease Models, Animal, Female, Immunohistochemistry, Inflammation, Lysophosphatidylcholines, Macrophages, RNA, Messenger, Spinal Cord Diseases, Toxins, Biological, Gene Expression, Cytokines, Rats, Sprague-Dawley, In Situ Hybridization, Recovery of Function, Reverse Transcriptase Polymerase Chain Reaction, CD11b Antigen, Microarray Analysis, Rats
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