Retinoid X receptor activation reverses age-related deficiencies in myelin debris phagocytosis and remyelination.

The efficiency of central nervous system remyelination declines with age. This is in part due to an age-associated decline in the phagocytic removal of myelin debris, which contains inhibitors of oligodendrocyte progenitor cell differentiation. In this study, we show that expression of genes involved in the retinoid X receptor pathway are decreased with ageing in both myelin-phagocytosing human monocytes and mouse macrophages using a combination of in vivo and in vitro approaches. Disruption of retinoid X receptor function in young macrophages, using the antagonist HX531, mimics ageing by reducing myelin debris uptake. Macrophage-specific RXRα (Rxra) knockout mice revealed that loss of function in young mice caused delayed myelin debris uptake and slowed remyelination after experimentally-induced demyelination. Alternatively, retinoid X receptor agonists partially restored myelin debris phagocytosis in aged macrophages. The agonist bexarotene, when used in concentrations achievable in human subjects, caused a reversion of the gene expression profile in multiple sclerosis patient monocytes to a more youthful profile and enhanced myelin debris phagocytosis by patient cells. These results reveal the retinoid X receptor pathway as a positive regulator of myelin debris clearance and a key player in the age-related decline in remyelination that may be targeted by available or newly-developed therapeutics.This work was supported by grants from the UK Multiple Sclerosis Society, Wellcome-Trust, NINDS/NIH Intramural Research Program, Health Research Board Scholars Program, Gates-Cambridge Scholarship, and Spanish Ministry of Economy and Competitiveness (SAF2012- 31483).S

Changes in the Oligodendrocyte Progenitor Cell Proteome with Ageing.

Following central nervous system (CNS) demyelination, adult oligodendrocyte progenitor cells (OPCs) can differentiate into new myelin-forming oligodendrocytes in a regenerative process called remyelination. Although remyelination is very efficient in young adults, its efficiency declines progressively with ageing. Here we performed proteomic analysis of OPCs freshly isolated from the brains of neonate, young and aged female rats. Approximately 50% of the proteins are expressed at different levels in OPCs from neonates compared with their adult counterparts. The amount of myelin-associated proteins, and proteins associated with oxidative phosphorylation, inflammatory responses and actin cytoskeletal organization increased with age, whereas cholesterol-biosynthesis, transcription factors and cell cycle proteins decreased. Our experiments provide the first ageing OPC proteome, revealing the distinct features of OPCs at different ages. These studies provide new insights into why remyelination efficiency declines with ageing and potential roles for aged OPCs in other neurodegenerative diseases

Retinoid X Receptor activation reverses age-related deficiencies in myelin debris phagocytosis and CNS remyelination

Remyelination is a regenerative process that occurs through the formation of myelin sheaths by oligodendrocytes, which are recruited as oligodendrocyte progenitor cells (OPCs) after demyelination in diseases such as Multiple Sclerosis (MS).A key environmental factor regulating OPC differentiation is the fate of myelin debris generated during demyelination. Myelin debris contains inhibitors of OPC differentiation and thus its clearance by phagocytic macrophages is an important component of creating a lesion environment conducive to remyelination. The efficiency of debris clearance declines with age, contributing to the age-associated decline in remyelination. Therefore, understanding the mechanisms of the age-related decline in myelin debris phagocytosis is important for devising means to therapeutically reverse the decline in remyelination. The aim of this study was to determine the functional/molecular differences between young and old phagocytes involved in myelin debris clearance, thereby identifying therapeutically modifiable pathways associated with efficient myelin debris phagocytosis. In this study, we show that expression of genes involved in the retinoid X receptor (RXR) and peroxisome proliferator-activated receptor (PPAR) pathways are decreased with ageing in both myelin-phagocytosing human monocytes and mouse macrophages. Disruption of RXR and PPAR using synthetic antagonists in young macrophages mimics ageing by reducing myelin debris uptake. Macrophage-specific RXRα knockout mice revealed that loss of RXR function in young mice caused delayed myelin debris uptake and slowed remyelination. Alternatively, receptor agonists partially restored myelin debris phagocytosis in aged macrophages. The FDA-approved agonists bexarotene and pioglitazone, when used in concentrations achievable in human subjects, caused a reversion of the gene expression profiles in MS patient monocytes to a more youthful profile and enhanced myelin debris phagocytosis by patient cells. Activation of these pathways also enhances immunoregulatory markers on monocytes from MS patients, further suggesting the regeneration-promoting capacity of activating these pathways in phagocytes. These results reveal the RXR/PPAR pathway as a positive regulator of myelin debris clearance and a key player in the age-related decline in remyelination that may be targeted by available or newly-developed therapeutics.This work was supported by the Gates-Cambridge Scholarship and NIH-Cambridge Partnership Progra

Aging restricts the ability of mesenchymal stem cells to promote the generation of oligodendrocytes during remyelination.

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) that leads to severe neurological deficits. Due to their immunomodulatory and neuroprotective activities and their ability to promote the generation of oligodendrocytes, mesenchymal stem cells (MSCs) are currently being developed for autologous cell therapy in MS. As aging reduces the regenerative capacity of all tissues, it is of relevance to investigate whether MSCs retain their pro-oligodendrogenic activity with increasing age. We demonstrate that MSCs derived from aged rats have a reduced capacity to induce oligodendrocyte differentiation of adult CNS stem/progenitor cells. Aging also abolished the ability of MSCs to enhance the generation of myelin-like sheaths in demyelinated cerebellar slice cultures. Finally, in a rat model for CNS demyelination, aging suppressed the capability of systemically transplanted MSCs to boost oligodendrocyte progenitor cell (OPC) differentiation during remyelination. Thus, aging restricts the ability of MSCs to support the generation of oligodendrocytes and consequently inhibits their capacity to enhance the generation of myelin-like sheaths. These findings may impact on the design of therapies using autologous MSCs in older MS patients.The authors would like to thank the following funding agencies for their support: Paracelsus Medical University PMU-FFF Long-Term Fellowship L-12/01/001-RIV (to and Stand-Alone Grant E-12/15/077-RIT (both to F.J.R.); Chilean Comisión Nacional de Investigación Científica y Tecnológica (CONICYT) FONDECYT Program Regular Grant Nº 1161787 (to F.J.R.), Regular Grant Nº 1141015 (to L.F.B.); Chilean CONICYT PCI Program Grant Nº REDES170233 (to F.J.R.), Grant Nº REDES180139 and Grant Nº REDI170037; Chilean CONICYT FONDEFIDeA Program Grant Nº ID17AM0043 (to M.E.S. and F.J.R.); European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreements N HEALTH-F2-2011-278850 (INMiND) and HEALTH-F2-2011-279288 (IDEA). The work in the Küry laboratory was supported by the German Research Foundation (DFG; KU1934/2_1, KU1934/5-1) and the Christiane and Claudia Hempel Foundation for clinical and iBrain. The work in the Franklin laboratory was supported by grants from the UK Multiple Sclerosis Society and the Adelson Medical Research Foundation, and a core support grant from the Wellcome Trust and MRC to the Wellcome-MRC Cambridge Stem Cell Institute. In addition, the present work was supported by the state of Salzburg (to L.A.). We thank Armin Schneider, Sygnis Pharma AG Heidelberg, Germany, for the MBP promoter construct. We disclose any conflict of interest

Brain-specific regulatory T cell expansion limits cognitive decline

Recent work from Lemaitre and colleagues leveraged a central nervous system (CNS)-specific gene delivery approach to expand regulatory T cells (Treg) in aged mice. CNS-restricted Treg expansion reversed age-related glial cell transcriptomic changes and prevented aspects of cognitive decline, unveiling immune modulation as a potential approach to protect cognitive function with age.This work was funded by the Maria Zambrano fellowship from Spanish Ministry of Science, Innovation and Universities, financed by European Union ‘NextGenerationEU’ (Universitat Autónoma de Barcelona) to M.L.S., the Miguel Servet Fellowship from the Spanish Health Institute Carlos III to A.G.F. (CP21/00032) and a grant from the Spanish State Research Agency (PID2021-124465OA-I00) to A.G.F.Peer reviewe

Glial cell alterations in diabetes-induced neurodegeneration

Type 2 diabetes mellitus is a global epidemic that due to its increasing prevalence worldwide will likely become the most common debilitating health condition. Even if diabetes is primarily a metabolic disorder, it is now well established that key aspects of the pathogenesis of diabetes are associated with nervous system alterations, including deleterious chronic inflammation of neural tissues, referred here as neuroinflammation, along with different detrimental glial cell responses to stress conditions and neurodegenerative features. Moreover, diabetes resembles accelerated aging, further increasing the risk of developing age-linked neurodegenerative disorders. As such, the most common and disabling diabetic comorbidities, namely diabetic retinopathy, peripheral neuropathy, and cognitive decline, are intimately associated with neurodegeneration. As described in aging and other neurological disorders, glial cell alterations such as microglial, astrocyte, and Müller cell increased reactivity and dysfunctionality, myelin loss and Schwann cell alterations have been broadly described in diabetes in both human and animal models, where they are key contributors to chronic noxious inflammation of neural tissues within the PNS and CNS. In this review, we aim to describe in-depth the common and unique aspects underlying glial cell changes observed across the three main diabetic complications, with the goal of uncovering shared glial cells alterations and common pathological mechanisms that will enable the discovery of potential targets to limit neuroinflammation and prevent neurodegeneration in all three diabetic complications. Diabetes and its complications are already a public health concern due to its rapidly increasing incidence, and thus its health and economic impact. Hence, understanding the key role that glial cells play in the pathogenesis underlying peripheral neuropathy, retinopathy, and cognitive decline in diabetes will provide us with novel therapeutic approaches to tackle diabetic-associated neurodegeneration