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ApoE in the brain is produced primarily by astrocytes; once secreted from these cells, apoE binds lipids and forms high\u2010density lipoprotein (HDL)\u2010like particles. Accumulation of amyloid\u2010\u03b2 protein (A\u03b2) in the brain is a key hallmark of AD, and is thought to initiate a pathogenic cascade leading to neurodegeneration and dementia. The level and lipidation state of apoE affect A\u03b2 aggregation and clearance pathways. Elevated levels of plasma HDL are associated with lower risk and severity of AD; the underlying mechanisms, however, have not been fully elucidated. This study was designed to investigate the impact of an HDL mimetic peptide, 4F, on the secretion and lipidation of apoE. We found that 4F significantly increases apoE secretion and lipidation in primary human astrocytes as well as in primary mouse astrocytes and microglia. Aggregated A\u03b2 inhibits glial apoE secretion and lipidation, causing accumulation of intracellular apoE, an effect that is counteracted by co\u2010treatment with 4F. Pharmacological and gene editing approaches show that 4F mediates its effects partially through the secretory pathway from the endoplasmic reticulum to the Golgi apparatus and requires the lipid transporter ATP\u2010binding cassette transporter A1. We conclude that the HDL mimetic peptide 4F promotes glial apoE secretion and lipidation and mitigates the detrimental effects of A\u03b2 on proper cellular trafficking and functionality of apoE. These findings suggest that treatment with such an HDL mimetic peptide may provide therapeutic benefit in AD.<\/jats:p><\/jats:sec><jats:sec><jats:label\/><jats:p>\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc14554-fig-0008-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><jats:p><jats:bold>Read the Editorial Highlight for this article on page<\/jats:bold>\u00a0<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/doi.org\/10.1111\/jnc.14595\">580<\/jats:ext-link>.<\/jats:p><\/jats:sec>","DOI":"10.1111\/jnc.14554","type":"journal-article","created":{"date-parts":[[2018,7,20]],"date-time":"2018-07-20T09:21:25Z","timestamp":1532078485000},"page":"647-662","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":51,"title":["High\u2010density lipoprotein mimetic peptide 4F mitigates amyloid\u2010\u03b2\u2010induced inhibition of apolipoprotein E secretion and lipidation in primary astrocytes and microglia"],"prefix":"10.1111","volume":"147","author":[{"given":"Dustin","family":"Chernick","sequence":"first","affiliation":[{"name":"Department of Pharmacology University of Minnesota Minneapolis Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Ortiz\u2010Valle","sequence":"additional","affiliation":[{"name":"Department of Pharmacology University of Minnesota Minneapolis Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Jeong","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Pharmacology University of Minnesota Minneapolis Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suresh K.","family":"Swaminathan","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics University of Minnesota Minneapolis Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karunya K.","family":"Kandimalla","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics University of Minnesota Minneapolis Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6276-248X","authenticated-orcid":false,"given":"G. 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