Loss Of Myelin Integrity Contributes To The Biology Of Brain Aging

Background and aims:The biology of brain aging is characterized by multiple changes in the neuronal cell structure,molecule,physiology and biophysics.In particular,brain aging often accompanies by a decreased neural plasticity than neuronal loss.However,identification of molecular markers for the biology of brain aging remains elusive.In the present study,we take advantage of the resource available to our institute and pursue this hypothesis in a non-human primate model,the macaque monkey.Methods:First,using Black-Gold ? staining to probe gray matter changes in macaques' brains at multiple states of brain development and aging.Also,We use 9.4T MRI to tracked and found age-related myelin regression and correlate it with brain volume of macaques.Second,we followed up these Black-Gold ? staining and MR imaging studies by probing the changes in cell biology that accompany them.This was the comprehensive effort to relate macroscopic changes in myelin that occur with age with functional deficits seen at the microscopic level.Third,we explored the accompanying molecular genetic changes that occur in the nuclei of the myelinating cells known as oligodendrocytes during aging by immunohistochemistry and RNAsope.Last,we performed immunofluorescence to observe the interaction between oligodendrocytes and other glial cells.Results:We explored the myelin anatomical structures and molecular processes in the prefrontal cortex of macaques during brain aging.First,Black gold ? staining shows the myelinated fibers may be reduced to some extent during normal aging in macaque prefrontal cortex.Then,we use 9.4T MRI to find that the volume of gray matter and white matter in the PFC of macaques increased with age and reached the peak at about 18 years old,followed by a decrease in both gray matter and white matter.Also,we found that the cortical myelin sheath increased until year 20 of ages,consistented with MRI results.We hypothesized that the loss of myelin sheath may be one of the reasons of brain aging.Next,we explored the molecular genetic changes of myelin cells and their progenitors according to the process of myelin formation.We find MBP positive cells in the prefrontal cortex of macaques,especially layer1,reduced during aging.The OLIG2-positive staining was used to detect the changes of Oligodendrocyte precursor cells(OPC)in the prefrontal cortex of rhesus monkeys.The results showed that OLIG2-positive cells remained highly active until 30 years of age,suggesting that the lifelong plasticity of the myelin sheath.Finally,we demonstrated that aging myelin fragments accumulate in microglia in macaques.Conclusion:Evidence suggests that loss of myelin and reduction of oligodendrocytes in prefrontal lobe of macaques during aging.