LOSS OF OLIGODENDROCYTES IS AN EARLY AMYLOID-INDEPENDENT EVENT IN THE PROGRESS OF DEMENTIA

Abstract

DNA damage and neuronal cell cycle re-entry are commonly observed during neurodegeneration in Alzheimer’s disease (AD). White matter (WM) degeneration is a recognized co-morbidity, but little is known about the underlying neurobiology. We hypothesize that oligodendrocyte loss (OL) occurs early in the process of dementia that is independent of amyloid. A cross sectional dataset of MRI data from healthy controls, individuals with mild cognitive impairment (MCI) or subjects with AD (n = 507) was obtained from the National Alzheimer’s Coordinating Center and Spearman’s correlational analysis was performed. Additional specimens from healthy controls, individuals with plaque-free dementia and others diagnosed as AD came from NeuroBioBank (n = 8 per group). These cases were examined by immunofluorescence. Gray matter (GM) and white matter (WM) volume declined with age as well as with MMSE. In MCI, the GM reduction was highly correlated with a reduced hippocampal volume (R = 0.42) and increased white matter hyperintensities (WMH; R = 0.49). We found no correlation with WM volume (R = 0.13). These findings, especially the MCI cohort, implicate myelin lesions as an early event in the onset of dementia. By immunocytochemistry, the number of actively myelinating oligodendrocytes (myelin regulatory factor [MyRF]-positive), mature OLs (myelin basic protein positive) or Olig2-positve OLs were signifcantly reduced in plaque-free dementia as well as in AD (p < 0.005). Moreover, 70% of the Olig2+ cells co-labelled with γH2A.X in the plaque-free dementia group, indicative of DNA damage (p = 0.006). In all dementia groups, 25% of the postmitotic MyRF+ cells stained with the cell cycle marker, cyclin D (p < 0.05); caspase-3 staining was found in the same areas. WMH in the aging population is an early correlate of neuronal loss and cognitive decline. The presence of OLs double stained for cyclin D and caspase-3 suggests that, just as in neurons, aberrant cell cycle re-entry is associated with OL cell death. Finally, the correlation of these events with dementia, but not with plaques implicates an amyloid independent mechanism as the root cause of the white matter abnormalities.