Unexpected central role of the androgen receptor in the spontaneous regeneration of myelin

Abstract

Lost myelin can be replaced after injury or during demyelinating diseases in a regenerative process called remyelination. In the central nervous system (CNS), the myelin sheaths, which protect axons and allow the fast propagation of electrical impulses, are produced by oligodendrocytes. The abundance and widespread distribution of oligodendrocyte progenitors (OPs) within the adult CNS account for this remarkable regenerative potential. Here, we report a key role for the male gonad, testosterone, and androgen receptor (AR) in CNS remyelination. After lysolecithin-induced demyelination of the male mouse ventral spinal cord white matter, the recruitment of glial fibrillary acidic protein-expressing astrocytes was compromised in the absence of testes and testosterone signaling via AR. Concomitantly, the differentiation of OPs into oligodendrocytes forming myelin basic protein (MBP) + and proteolipid protein-positive myelin was impaired. Instead, in the absence of astrocytes, axons were remyelinated by protein zero (P0) + and peripheral myelin protein 22-kDa (PMP22) + myelin, normally only produced by Schwann cells in the peripheral nervous system. Thus, testosterone favors astrocyte recruitment and spontaneous oligodendrocyte-mediated remyelination. This finding may have important implications for demyelinating diseases, psychiatric disorders, and cognitive aging. The testosterone dependency of CNS oligodendrocyte remyelination may have roots in the evolutionary history of the AR, because the receptor has evolved from an ancestral 3-ketosteroid receptor through gene duplication at the time when myelin appeared in jawed vertebrates.T he remyelination of axons is a complex process, involving interactions between different types of neural cells. It shows a peculiarity that has been observed in both experimental models and demyelinating diseases such as multiple sclerosis (MS) (1). Although most of the remyelination is normally accomplished by oligodendrocytes derived from oligodendrocyte progenitors (OPs), a variable proportion of central nervous system (CNS) axons can be remyelinated by cells with the immunophenotypic and ultrastructural characteristics of Schwann cells, the presence of which is normally limited to the peripheral nervous system (PNS). These cells indeed express protein zero (P0), a sensitive and specific marker of Schwann cells (2). Moreover, analysis by electron microscopy demonstrated that they have the typical morphology of myelinating Schwann cells (1-4). These ultrastructural findings indicate that the expression of P0 by part of the remyelinating cells is not merely ectopic, but that these cells may correspond to authentic Schwann cells. This observation was further supported by their expression of Schwann cell-specific transcription factors (5).Importantly, there is strong evidence that large numbers of the Schwann cells present in demyelinating CNS lesions are derived from OPs. The first evidence came from the transplantation of purified OPs into demyelinating CNS lesions, in which endogenous ...

The role of testosterone in MS risk and course

“…Using a lysolecithin model, investigators found that testosterone and androgen receptors are required for spontaneous remyelination. 22 …”

Epimedii Herba: A Promising Herbal Medicine for Neuroplasticity

“…Furthermore, the Kawato research group reported that gonadal hormones, including estradiol, testosterone, and DHT, are produced at hippocampal lesions and act as modulators of synaptic plasticity (Ish et al ., ; Kawato, ). Additionally, testosterone might also be involved in spontaneous myelin regeneration (Bielecki et al ., ). One clinical study suggested that the level of testosterone was important for physical and cognitive rehabilitation (Rosario et al ., ).…”

On elucidation of the role of mitochondria dysfunction and oxidative stress in multiple sclerosis

“…Indeed, testosterone treatment can prevent and even reverse neurodegeneration associated with MS . Testosterone has been found to promote myelin formation and regeneration . Testosterone treatment of MS patients has been found to significantly suppress PBMC production of IL‐2 while increasing TGFbeta1 production .…”

“…197,198 Testosterone has been found to promote myelin formation and regeneration. [199][200][201][202] Testosterone treatment of MS patients has been found to significantly suppress PBMC production of IL-2 while increasing TGFbeta1 production. 203 In addition, evidence indicates that estrogen, progesterone, and testosterone treatment improve cognitive functions in MS patients.…”