Characterizing the morphological and cellular effects of amyloid-beta on oligodendroglia and myelination
Date
2022
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Abstract
Loss of white matter integrity is a feature of natural aging and Alzheimer’s disease (AD).Notably, the spread of AD pathology reflects the pattern of myelination during normal
development but in reverse (neuropathologic retrogenesis), where later myelinated brain regions
develop AD pathology before early myelinated regions. Classical neuropathologic changes in AD
(i.e. accumulation of soluble oligomeric amyloid-β) are correlated with progressive neuronal
death, but may also induce changes in the cells of the oligodendroglia lineage and damage myelin.
This project sought to elucidate the cellular responses of the oligodendroglia cells to
amyloid-β (Aβ) and the subsequent impact on white matter structure. Using neonatal C57BL/6J
mice, we were able to establish a variety of primary glial cultures: oligodendrocyte precursor cells
(OPC) and oligodendrocytes cultures. We assessed the effects of Aβ on OPC survival as well as
their proliferation using TUNEL and EdU detection assays. These preliminary results indicate that
exposure to 1 μM Aβ1-42 for 5 days is sufficient to reduce OPC proliferation but not induce
apoptosis. Interestingly, we found that a small population of OPCs seemingly switch glial fates to
type II astrocytes indicated by the loss of typical OPC morphology concomitant with the induction
of expression of the glial fibrillary acid protein (GFAP). We further investigated the effects Aβ
may have on the mature oligodendrocyte, where cultures treated with Aβ displayed decreased
MBP intensity and changes in the number of processes. Using ex vivo organotypic brain slices, we
were able to corroborate the changes in MBP intensity seen in the in vitro cultures, but unable to
discern direct changes in axon myelination. However, immunoblots of hippocampal lysates from
5XFAD mice compared to age-matched wild-type mice demonstrated alterations in myelin protein
levels.
Our preliminary results showcasing the effects of Aβ on cells of the oligodendroglia lineage
and CNS white matter suggest that impaired myelin maintenance leading to demyelination may be
more prominent in AD than previously thought. Hence, characterizing changes in white matter
alterations due to AD-related pathogenesis beyond the normal aging process is key to furthering
our understanding of AD pathology.
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Neurosciences, amyloid-β, myelin, oligodendrocyte, oligodendrocyte precursor cell, white matter
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72 pages
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