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Publication : Apolipoprotein E ε4 Mediates Myelin Breakdown by Targeting Oligodendrocytes in Sporadic Alzheimer Disease.

First Author  Cheng GW Year  2022
Journal  J Neuropathol Exp Neurol Volume  81
Issue  9 Pages  717-730
PubMed ID  35779013 Mgi Jnum  J:347233
Mgi Id  MGI:7616624 Doi  10.1093/jnen/nlac054
Citation  Cheng GW, et al. (2022) Apolipoprotein E epsilon4 Mediates Myelin Breakdown by Targeting Oligodendrocytes in Sporadic Alzheimer Disease. J Neuropathol Exp Neurol 81(9):717-730
abstractText  White matter degradation in the frontal lobe is one of the earliest detectable changes in aging and Alzheimer disease. The epsilon4 allele of apolipoprotein E (APOE4) is strongly associated with such myelin pathology but the underlying cellular mechanisms remain obscure. We hypothesized that, as a lipid transporter, APOE4 directly triggers pathology in the cholesterol-rich myelin sheath independent of AD pathology. To test this, we performed immunohistochemistry on brain tissues from healthy controls, sporadic, and familial Alzheimer disease subjects. While myelin basic protein expression was largely unchanged, in frontal cortex the number of oligodendrocytes (OLs) was significantly reduced in APOE4 brains independent of their Braak stage or NIA-RI criteria. This high vulnerability of OLs was confirmed in humanized APOE3 or APOE4 transgenic mice. A gradual decline of OL numbers was found in the aging brain without associated neuronal loss. Importantly, the application of lipidated human APOE4, but not APOE3, proteins significantly reduced the formation of myelinating OL in primary cell culture derived from Apoe-knockout mice, especially in cholesterol-depleted conditions. Our findings suggest that the disruption of myelination in APOE4 carriers may represent a direct OL pathology, rather than an indirect consequence of amyloid plaque formation or neuronal loss.
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