期刊
JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY
卷 81, 期 9, 页码 717-730出版社
OXFORD UNIV PRESS INC
DOI: 10.1093/jnen/nlac054
关键词
Alzheimer disease; Amyloid-independent; APOE4; Lipid transport; Myelin; Oligodendrocyte
资金
- General Research Fund (Research Grant Council, Hong Kong SAR) [GRF16124916]
- Department of Neurobiology, University of Pittsburgh
- Australian National Health and Medical Research Fund [APP1160691]
- National Institute on Aging (NIA) [P30 AG066468]
- NIA [R01 AG069912, P50 AG005133]
White matter degradation in the frontal lobe is an early detectable change in aging and Alzheimer's disease, and the APOE4 gene is strongly associated with this degradation. Research has found that APOE4 directly triggers myelin pathology rich in cholesterol, rather than being an indirect consequence of amyloid plaque formation or neuronal loss.
White matter degradation in the frontal lobe is one of the earliest detectable changes in aging and Alzheimer disease. The epsilon 4 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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