Cognitive decline remains an unaddressed problem for the elderly. We show that myelination is highly active in young mice and greatly inhibited in aged mice, coinciding with spatial memory deficits. Inhibiting myelination by deletion of Olig2 in oligodendrocyte precursor cells impairs spatial memory in young mice, while enhancing myelination by deleting the muscarinic acetylcholine receptor 1 in oligodendrocyte precursor cells, or promoting oligodendroglial differentiation and myelination via clemastine treatment, rescues spatial memory decline during aging. Preventing age-related cognitive decline represents an unmet need for the elderly 1. Multiple lines of magnetic resonance imaging evidence have identified abnormalities in the white matter of aged human brains 2. Recent studies have revealed that myelin remodeling persists

No abstract

Exposure to chronic hypoxia is considered to be a risk factor for deficits in brain function in adults, but the underlying mechanisms remain largely unknown. Since active myelinogenesis persists in the adult central nervous system, here we aimed to investigate the impact of chronic hypoxia on myelination and the related functional consequences in adult mice. Using a transgenic approach to label newly-generated myelin sheaths (NG2-CreERTM; Tau-mGFP), we found that myelinogenesis was highly active in most brain regions, such as the motor cortex and corpus callosum. After exposure to hypoxia (10% oxygen) 12 h per day for 4 weeks, myelinogenesis was largely inhibited in the 4-month old brain and the mice displayed motor coordination deficits revealed by the beam-walking test. To determine the relationship between the inhibited myelination and functional impairment, we induced oligodendroglia-specific deletion of the transcription factor Olig2 by tamoxifen (NG2-CreERTM; Tau-mGFP; Olig2 fl/fl) in adult mice to mimic the decreased myelinogenesis caused by hypoxia. The deletion of Olig2 inhibited myelinogenesis and consequently impaired motor coordination, suggesting that myelinogenesis is required for motor function in adult mice. To understand whether enhancing myelination could protect brain functions against hypoxia, we treated hypoxic mice with the myelination-enhancing drug-clemastine, which resulted in enhanced myelogenesis and improved motor coordination. Taken together, our data indicate that chronic hypoxia inhibits myelinogenesis and causes functional deficits in the brain and that enhancing myelinogenesis protects brain functions against hypoxia-related deficits.

Oligodendrocytes (OLs) are a major type of glial cells in the central nervous system that generate multiple myelin sheaths to wrap axons. Myelin ensures fast and efficient propagation of action potentials along axons and supports neurons with nourishment. The decay of OLs and myelin has been implicated in age-related neurodegenerative diseases and these changes are generally considered as an inevitable result of neuron loss and axon degeneration. Noticeably, OLs and myelin undergo dynamic changes in healthy adult brains, that is, newly formed OLs are continuously added throughout life from the differentiation of oligodendrocyte precursor cells (OPCs) and the pre-existing myelin sheaths may undergo degeneration or remodeling. Increasing evidence has shown that changes in OLs and myelin are present in the early stages of neurodegenerative diseases, and even prior to significant neuronal loss and functional deficits. More importantly, oligodendroglia-specific manipulation, by either deletion of the disease gene or enhancement of myelin renewal, can alleviate functional impairments in neurodegenerative animal models. These findings underscore the possibility that OLs and myelin are not passively but actively involved in neurodegenerative diseases and may play an important role in modulating neuronal function and survival. In this review, we summarize recent work characterizing by OLs and myelin changes in both healthy and neurodegenerative brains and discuss the potential of targeting oligodendroglial cells in treating neurodegenerative diseases.