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The \u03b54 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.<\/jats:p>","DOI":"10.1093\/jnen\/nlac054","type":"journal-article","created":{"date-parts":[[2022,7,2]],"date-time":"2022-07-02T13:06:53Z","timestamp":1656767213000},"page":"717-730","source":"Crossref","is-referenced-by-count":36,"title":["Apolipoprotein E \u03b54 Mediates Myelin Breakdown by Targeting Oligodendrocytes in Sporadic Alzheimer Disease"],"prefix":"10.1093","volume":"81","author":[{"given":"Gerald Wai-Yeung","family":"Cheng","sequence":"first","affiliation":[{"name":"From the , Hong Kong SAR"},{"name":"Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Kowloon , Hong Kong SAR"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kingston King-Shi","family":"Mok","sequence":"additional","affiliation":[{"name":"From the , Hong Kong SAR"},{"name":"Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Kowloon , Hong Kong SAR"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunny Hoi-Sang","family":"Yeung","sequence":"additional","affiliation":[{"name":"From the , Hong Kong SAR"},{"name":"Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Kowloon , Hong Kong SAR"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Kofler","sequence":"additional","affiliation":[{"name":"Division of Neuropathology, School of Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl","family":"Herrup","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, School of Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania, 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