Myelin Across Lifespan: From Establishing Internodal Length in Development to Maintenance with Vitamin B12 in Aging

Abstract

Oligodendrocytes wrap axons to make myelin in the central nervous system for saltatory conduction. The length of these wraps, or internodes, influences the axonal conduction speed and thus plays a direct role in neuronal function and synchronicity. Yet we don't have a clear understanding about how these patterns are determined and maintained through life. To answer this question, we used the mouse models PLP-CreER^T;STARS and NG2-CreER^T;tau^mGFP to study how the timing of differentiation and visual stimulation impact internodal length in the optic nerve. Moreover, we assessed the effect of serum vitamin B12 levels on myelin maintenance by testing myelin and neurocognitive integrity (visual evoked potentials [VEP], cognitive testing, MRI and serological biomarkers) in a cohort of aging healthy human adults. We found that in the optic nerve of mice, internodes made by early differentiating oligodendrocytes increase in average length (p=0.002) and count (p=0.038) for about one week but then remain stable into adulthood. Later differentiating oligodendrocytes make shorter but more numerous internodes (p<0.0001). Dark rearing the mice increased the average internodal length (p<0.0001). In aging humans, we found that lower (but within the normal range) B12 levels are associated with increased VEP latency (p=0.023), worsened cognitive performance (p=0.006), and increased volume of white matter hyperintensities in the brain (p=0.039). However, higher levels of holo-haptocorrin (biologically unavailable B12 fraction) were associated with higher levels of Tau and Ubiquitin carboxy-terminal hydrolase (UCH)-L1 proteins in the serum (p=0.015 and 0.022 respectively). With this work we show that the timing of oligodendrocyte differentiation and the presence of visual stimulation contribute to the determination of internodal length and count during development. Once established, the average internodal length remains stable. Moreover, vitamin B12 levels have an effect on myelin maintenance and cognitive function in aging human adults.