Age-related changes in human and non-human primate white matter: from myelination disturbances to cognitive decline

Kohama, Steven G.; Rosene, Douglas L.; Sherman, Larry S.

doi:10.1007/s11357-011-9357-7

Cited by 121 publications

(101 citation statements)

References 175 publications

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“…The decreased expression was due, at least in part, via the hypermethylation of the KL promoter (King et al 2012a). Decreased levels of KL correlate with ubiquitous dysmyelination observed in the brains of aged monkeys by us as well as by other groups (Sloane et al 2003;Hinman et al 2006;Hinman and Abraham 2007;Makris et al 2007;Wisco et al 2008;Bowley et al 2010;Kohama et al 2012). In support of a possible involvement of KL in myelination of the CNS, we have reported that KL-KO mice exhibited severely impaired myelination of the optic nerve and corpus callosum accompanied by significant abnormalities at the nodes of Ranvier.…”

Section: Introductionsupporting

confidence: 57%

The Anti-Aging Protein Klotho Enhances Remyelination Following Cuprizone-Induced Demyelination

Zeldich

Chen

Avila³

et al. 2015

J Mol Neurosci

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The current study examined whether overexpression of Klotho (KL) in transgenic mice can enhance remyelination following cuprizone-induced demyelination and improves the clinical outcome in experimental autoimmune encephalomyelitis (EAE). Demyelination was achieved by feeding transgenic mice overexpressing the transmembrane form of Klotho (KL-OE) and wild-type (WT) littermates cuprizone-containing chow for 6 weeks. The animals were then allowed to remyelinate for 3 weeks. Paraphenylenediamine staining and platelets-derived growth factor receptor α (PDGFRα) and glutathione S-transferase pi (GSTpi) immunohistochemistry were performed on corpus callosum (CC) sections for quantification of myelin and progenitor and mature oligodendrocytes, respectively. The EAE model was induced with the MOG35-55 peptide. The animals were scored daily for clinical symptoms for 30 days. Following 6 weeks of demyelination, both KL-OE mice and WT littermates demonstrated almost complete and comparable demyelination of the CC. However, the level of spontaneous remyelination was increased approximately two-fold in KL-OE mice, although no significant differences in the numbers of PDGFRα and GSTpi-positive cells were observed. Following EAE induction, Klotho overexpression did not affect the clinical scores, likely due to the different roles Klotho plays in the brain and spinal cord. Thus, increasing Klotho expression should be considered as a therapy for enhancing remyelination in the brains of individuals with multiple sclerosis.

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Section: Introductionsupporting

confidence: 57%

The Anti-Aging Protein Klotho Enhances Remyelination Following Cuprizone-Induced Demyelination

Zeldich

Chen

Avila³

et al. 2015

J Mol Neurosci

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“…Studies of the effects of age on microglia have reported that microglial activation increases with age (Henry et al 2009). It has also been noted that activation occurs primarily in white matter rather than gray matter (Hart et al 2012) and, in the monkey, is associated with cognitive impairment (Sloane et al 1999; for review, see Kohama et al 2011;Peters and Kemper 2012).…”

Section: Introductionmentioning

confidence: 99%

Microglia activation and phagocytosis: relationship with aging and cognitive impairment in the rhesus monkey

et al. 2017

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While cognitive decline is observed in the normal aging monkey, neurons are not lost with age. Instead, frontal white matter is lost as myelin degenerates and both correlate with age-related cognitive decline. As age-related myelin damage increases, there should be an increase in clearance of damaged myelin by microglial phagocytosis. In this study, brains of behaviorally tested rhesus monkeys were assessed using unbiased stereology to quantify the density of activated microglia (LN3 antibody positive) and phagocytic microglia (galectin-3 (Gal-3) antibody positive) in three white matter regions: the corpus callosum, cingulum bundle (CGB), and frontal white matter (FWM). LN3 cell density was significantly increased in the CGB, whereas Gal-3 cell density was significantly increased in all regions. Increases in Gal-3 cell density in the FWM were associated with cognitive impairment. In the FWM of old animals, Gal-3-positive microglia were classified by morphological subtype as ramified, hypertrophic, or amoeboid. The densities of hypertrophic and amoeboid microglia significantly correlated with cognitive impairment. Finally, microglia were double-labeled with LN3 and Gal-3 showing that 91% of Gal-3 cells were also LN3 positive, thus expressing an Bactivated^phenotype. Furthermore, 15% of all double-labeled cells formed phagocytic cups. Overall, these results suggest that microglia become activated in white matter with age where the majority express a phagocytic phenotype. We hypothesize that age-related phagocytic activation of microglia is a response to accumulating myelin pathology. The association of Gal-3 in the FWM with cognitive impairment may reflect regional differences in damage or dysfunction of normal clearance mechanisms.

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“…On the other hand, if proBDNF is the intermediate protein, the reduced proBDNF would be a result of the neuron compensating to preserve mBDNF levels and signaling to preserve the cell and synapse. However, the decreased action potential conduction due to myelin damage would decrease the ability of the mBDNF to act on the synapse leading to the loss of the spines and axon (Kohama et al 2012).…”

Section: Bdnf and Normal Agingmentioning

confidence: 99%

“…This in turn could decrease trophic factor feedback. Since BDNF supports the axon (for review see (Poo 2001)), decreased trophic feedback from the postsynaptic cell to the axon could cause the retraction of the axon and the axonal loss visible in the white matter as discussed by Kohama et al 2012. The decreased trophic feedback could also be reflected in reported decreases in the number of dendritic spines and synapses on the postsynaptic cells (Dickstein et al 2013).…”

Section: Sex Differences In Bdnf Expressionmentioning

confidence: 99%

Candidate molecular pathways of white matter vulnerability in the brain of normal aging rhesus monkeys

2018

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Mammalian aging is associated with decline in cognitive functions. Studies searching for a cause of cognitive aging initially focused on neuronal loss but quantitative investigations of rat, monkey, and human brain using stereology demonstrated that in normal aging, unlike in neurodegenerative disease, neurons are not lost. Instead, electron microscopic and MRI studies in normal aging monkeys revealed age-related damage to myelin sheaths, loss of axons, and reduction in white matter volume which correlates with cognitive impairments. However, little is known about the cause of myelin defects or associated axon loss. The present study investigates the effect of age on signaling pathways between oligodendroglia and neurons using a custom PCR array to assess the expression of 87 genes of interest in cortical gray matter and white matter from the inferior parietal lobe (IPL) of normal rhesus monkeys ranging in age from 4.2 to 30.4 years old. From this array data, five target genes of interest were selected for further analysis to confirm gene expression and measure protein expression. The most interesting target gene identified is brain-derived neurotrophic factor (BDNF), which was the only gene that was altered at both mRNA and protein levels. In gray matter, BDNF mRNA was decreased. While the level of the mature form of the protein was unchanged, there was a specific decrease in the precursor form of BDNF. These alterations in the BDNF in gray matter could contribute to the vulnerability and loss of the axons with age.

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Age-related changes in human and non-human primate white matter: from myelination disturbances to cognitive decline

Cited by 121 publications

References 175 publications

The Anti-Aging Protein Klotho Enhances Remyelination Following Cuprizone-Induced Demyelination

The Anti-Aging Protein Klotho Enhances Remyelination Following Cuprizone-Induced Demyelination

Microglia activation and phagocytosis: relationship with aging and cognitive impairment in the rhesus monkey

Candidate molecular pathways of white matter vulnerability in the brain of normal aging rhesus monkeys

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