Age‐related molecular reorganization at the node of Ranvier

Abstract

In myelinated axons, action potential conduction is dependent on the discrete clustering of ion channels at specialized regions of the axon, termed nodes of Ranvier. This organization is controlled, at least in part, by the adherence of myelin sheaths to the axolemma in the adjacent region of the paranode. Age-related disruption in the integrity of internodal myelin sheaths is welldescribed and includes splitting of myelin sheaths, redundant myelin, and fluctuations in biochemical constituents of myelin. These changes have been proposed to contribute to agerelated cognitive decline since in previous studies of monkeys, myelin changes correlate with cognitive performance. In the present study, we hypothesize that age-dependent myelin breakdown results in concomitant disruption at sites of axoglial contact, in particular at the paranode and that this disruption alters the molecular organization in this region. In aged monkey and rat optic nerves, immunolabeling for voltage-dependent potassium channels of the Shaker family (Kv1.2), normally localizing in the adjacent juxtaparanode, were mislocalized to the paranode. Similarly, immunolabeling for the paranodal marker, caspr, reveals irregular casprlabeled paranodal profiles, suggesting there may be age-related changes in paranodal structure. Ultrastructural analysis of paranodal segments from optic nerve of aged monkeys shows that in a subset of myelinated axons with thick sheaths, some paranodal loops fail to contact the axolemma. Thus, age-dependent myelin alterations affect axonal protein localization and may be detrimental to maintenance of axonal conduction.

Promoter methylation and age-related downregulation of Klotho in rhesus monkey

“…; Student's t-test, *p≤0.05) (Sloane et al 1999(Sloane et al , 2000 and develop inclusions (Luebke et al 2010). Myelin proteins are aberrantly expressed or degraded (Hinman and Abraham 2007;Hinman et al 2006Hinman et al , 2008Sloane et al 2003). Protein abnormalities accompany an overall loss of myelinated fibers and an increase in fibers with major myelin deficits like ballooning (Luebke et al 2010;Peters 2009).…”

“…Protein abnormalities accompany an overall loss of myelinated fibers and an increase in fibers with major myelin deficits like ballooning (Luebke et al 2010;Peters 2009). The overall number of oligodendrocytes increases with age, but when this increase is coupled to changes in action potential frequency along axons and reorganization of the nodes of Ranvier, it suggests attempts to compensate for widespread dysfunction (Chang et al 2005;Hinman et al 2006;Luebke et al 2010;Peters 2009). This study shows that in the same monkeys where KL protein is decreased, the KL promoter is modified by methylation but not oxidation.…”

Abnormal Indices of Cell Cycle Activity in Schizophrenia and their Potential Association with Oligodendrocytes

“…Such a mechanism has been posited to exist in the brains of aged non-human primates (Peters, 2002;Peters andSethares, 2003, 2004;Hinman et al, 2006). As such, another question that needs to be addressed is identifying the specific markers that distinguish these mitotically active cells.…”

Loss-of-function GJA12/Connexin47 mutations cause Pelizaeus–Merzbacher-like disease

“…Frozen paraformaldehyde-fixed rhesus monkey optic nerve and medulla (gift of Dr. Douglas Rosene, (Hinman et al 2006) was embedded in OCT and processed for immunofluorescence and immunoperoxidase staining as previously described (Kleopa et al 2004). Sections immunostained with the above Cx47 antibodies were double-labeled with rabbit antisera raised against aspartoacylase (ASPA; gift of Dr. James Garbern, (Madhavarao et al 2005); diluted 1:1000), Cx43 (Chemicon, Intl., Temecula, CA; diluted 1:2000), or monoclonal antibodies against GFAP (gift of Dr. Virginia Lee, University of Pennsylvania, Philadelphia, PA; diluted 1:10) or Cx43 (Chemicon, Intl., Temecula, CA; diluted 1:250).…”