{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T05:53:24Z","timestamp":1778565204150,"version":"3.51.4"},"reference-count":39,"publisher":"SAGE Publications","issue":"1","license":[{"start":{"date-parts":[[2023,1,3]],"date-time":"2023-01-03T00:00:00Z","timestamp":1672704000000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAD"],"published-print":{"date-parts":[[2023,1,3]]},"abstract":"<jats:p>Background: Macrophages of healthy subjects have a pro-resolution phenotype, upload amyloid-\u03b2 (A\u03b2) into endosomes, and degrade A\u03b2, whereas macrophages of patients with Alzheimer\u2019s disease (AD) generally have a pro-inflammatory phenotype and lack energy for brain clearance of A\u03b2. Objective: To clarify the pathogenesis of sporadic AD and therapeutic effects of polyunsaturated fatty acids (PUFA) with vitamins B and D and antioxidants on monocyte\/macrophage (MM) migration in the AD brain, MM transcripts in energy and A\u03b2 degradation, MM glycome, and macrophage clearance of A\u03b2. Methods: We followed for 31.3 months (mean) ten PUFA-supplemented neurodegenerative patients: 3 with subjective cognitive impairment (SCI), 2 with mild cognitive impairment (MCI), 3 MCI\/vascular cognitive impairment, 2 with dementia with Lewy bodies, and 7 non-supplemented caregivers. We examined: monocyte migration in the brain and a blood-brain barrier model by immunochemistry and electron microscopy; macrophage transcriptome by RNAseq; macrophage glycome by N-glycan profiling and LTQ-Orbitrap mass spectrometry; and macrophage phenotype and phagocytosis by immunofluorescence. Results: MM invade A\u03b2 plaques, upload but do not degrade A\u03b2, and release A\u03b2 into vessels, which develop cerebrovascular amyloid angiopathy (CAA); PUFA upregulate energy and A\u03b2 degradation enzyme transcripts in macrophages; PUFA enhance sialylated N-glycans in macrophages; PUFA reduce oxidative stress and increase pro-resolution MM phenotype, mitochondrial membrane potential, and A\u03b2 phagocytosis (p\u200a&lt;\u200a0.001). Conclusion: Macrophages of SCI, MCI, and AD patients have interrelated defects in the transcriptome, glycome, A\u03b2 phagocytosis, and A\u03b2 degradation. PUFA mend macrophage transcriptome, enrich glycome, enhance A\u03b2 clearance, and benefit the cognition of early-stage AD patients.<\/jats:p>","DOI":"10.3233\/jad-220764","type":"journal-article","created":{"date-parts":[[2022,11,8]],"date-time":"2022-11-08T11:40:55Z","timestamp":1667907655000},"page":"245-261","source":"Crossref","is-referenced-by-count":7,"title":["Polyunsaturated Fatty Acids Mend Macrophage Transcriptome, Glycome, and Phenotype in the Patients with Neurodegenerative Diseases, Including Alzheimer\u2019s Disease"],"prefix":"10.1177","volume":"91","author":[{"given":"Mary","family":"Dover","sequence":"first","affiliation":[{"name":"Department of Molecular, Cell and Developmental Biology, UCLA School of Life Sciences, Los Angeles, CA, USA"},{"name":"Department of Integrated Biology and Physiology, UCLA School of Life Sciences, Los Angeles, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Taylor","family":"Moseley","sequence":"additional","affiliation":[{"name":"Department of Molecular, Cell and Developmental Biology, UCLA School of Life Sciences, Los Angeles, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adrienne","family":"Biskaduros","sequence":"additional","affiliation":[{"name":"Department of Molecular, Cell and Developmental Biology, UCLA School of Life Sciences, Los Angeles, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mousumi","family":"Paulchakrabarti","sequence":"additional","affiliation":[{"name":"GlycoAnalytics Core, University of California SanDiego Health Sciences, La Jolla, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sung Hee","family":"Hwang","sequence":"additional","affiliation":[{"name":"Department of Entomology and Nematology, and UCDavis Comprehensive Cancer Center, University of California \u2013 Davis, Davis, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bruce","family":"Hammock","sequence":"additional","affiliation":[{"name":"Department of Entomology and Nematology, and UCDavis Comprehensive Cancer Center, University of California \u2013 Davis, Davis, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Biswa","family":"Choudhury","sequence":"additional","affiliation":[{"name":"GlycoAnalytics Core, University of California SanDiego Health Sciences, La Jolla, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karolina El\u017cbieta","family":"Kaczor-Urbanowicz","sequence":"additional","affiliation":[{"name":"UCLA Institute for Quantitative and Computational Biosciences, UCLA, Los Angeles, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrzej","family":"Urbanowicz","sequence":"additional","affiliation":[{"name":"Institute of Control and Computation Engineering, Warsaw University of Technology, Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marco","family":"Morselli","sequence":"additional","affiliation":[{"name":"Department of Molecular, Cell and Developmental Biology, UCLA School of Life Sciences, Los Angeles, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Johnny","family":"Dang","sequence":"additional","affiliation":[{"name":"Department of Molecular, Cell and Developmental Biology, UCLA School of Life Sciences, Los Angeles, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matteo","family":"Pellegrini","sequence":"additional","affiliation":[{"name":"Department of Molecular, Cell and Developmental Biology, UCLA School of Life Sciences, Los Angeles, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ketema","family":"Paul","sequence":"additional","affiliation":[{"name":"Department of Integrated Biology and Physiology, UCLA School of Life Sciences, Los Angeles, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laurent A.","family":"Bentolila","sequence":"additional","affiliation":[{"name":"Advanced Light Microscopy and Spectroscopy Laboratory, California Nano Systems Institute, UCLA, Los Angeles, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Milan","family":"Fiala","sequence":"additional","affiliation":[{"name":"Department of Molecular, Cell and Developmental Biology, UCLA School of Life Sciences, Los Angeles, CA, USA"},{"name":"Department of Integrated Biology and Physiology, UCLA School of Life Sciences, Los Angeles, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"179","reference":[{"key":"10.3233\/JAD-220764_ref1","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1126\/science.1072994","article-title":"The amyloid hypothesis of Alzheimer\u2019s disease: Progress and problems on the road to therapeutics","volume":"297","author":"Hardy","year":"2002","journal-title":"Science"},{"key":"10.3233\/JAD-220764_ref2","doi-asserted-by":"crossref","first-page":"1177","DOI":"10.1016\/j.cell.2017.05.038","article-title":"An expanded view of complex traits: From polygenic to omnigenic","volume":"169","author":"Boyle","year":"2017","journal-title":"Cell"},{"key":"10.3233\/JAD-220764_ref3","doi-asserted-by":"crossref","first-page":"12849","DOI":"10.1073\/pnas.0701267104","article-title":"Innate immunity and transcription of MGAT-III and Toll-like receptors in Alzheimer\u2019s disease patients are improved by bisdemethoxycurcumin","volume":"104","author":"Fiala","year":"2007","journal-title":"Proc Natl Acad Sci U S A"},{"key":"10.3233\/JAD-220764_ref4","doi-asserted-by":"crossref","first-page":"3210","DOI":"10.1172\/JCI90603","article-title":"Understanding the functions and relationships of the glymphatic system and meningeal lymphatics","volume":"127","author":"Louveau","year":"2017","journal-title":"J Clin Invest"},{"key":"10.3233\/JAD-220764_ref5","doi-asserted-by":"crossref","first-page":"1599","DOI":"10.1016\/S0002-9440(10)65476-4","article-title":"Microglial and astrocyte chemokines regulate monocyte migration through the blood-brain barrier in human immunodeficiency virus-1 encephalitis","volume":"155","author":"Persidsky","year":"1999","journal-title":"Am J Pathol"},{"key":"10.3233\/JAD-220764_ref6","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1016\/j.neurobiolaging.2006.12.001","article-title":"Degradation of fibrillar forms of Alzheimer\u2019s amyloid beta-peptide by macrophages","volume":"29","author":"Majumdar","year":"2008","journal-title":"Neurobiol Aging"},{"key":"10.3233\/JAD-220764_ref7","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.jneuroim.2009.02.015","article-title":"Immune blood biomarkers of Alzheimer disease patients","volume":"210","author":"Avagyan","year":"2009","journal-title":"J Neuroimmunol"},{"key":"10.3233\/JAD-220764_ref8","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1096\/fj.201600677rr","article-title":"Increased intermediate M1-M2 macrophage polarization and improved cognition in mild cognitive impairment patients on omega-3 supplementation","volume":"31","author":"Famenini","year":"2017","journal-title":"FASEB J"},{"key":"10.3233\/JAD-220764_ref9","doi-asserted-by":"crossref","first-page":"4359","DOI":"10.1096\/fj.201700290R","article-title":"Omega-3 fatty acids increase the unfolded protein response and improve amyloid-beta phagocytosis by macrophages of patients with mild cognitive impairment","volume":"31","author":"Olivera-Perez","year":"2017","journal-title":"FASEB J"},{"key":"10.3233\/JAD-220764_ref10","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1111\/nan.12472","article-title":"Review: Vascular dementia: Clinicopathologic and genetic considerations","volume":"44","author":"Vinters","year":"2018","journal-title":"Neuropathol Appl Neurobiol"},{"key":"10.3233\/JAD-220764_ref11","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1038\/s41583-019-0132-6","article-title":"Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease","volume":"20","author":"Butterfield","year":"2019","journal-title":"Nat Rev Neurosci"},{"key":"10.3233\/JAD-220764_ref12","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.3233\/JAD-170543","article-title":"Oxidative stress, amyloid-beta peptide, and altered key molecular pathways in the pathogenesis and progression of Alzheimer\u2019s disease","volume":"62","author":"Butterfield","year":"2018","journal-title":"J Alzheimers Dis"},{"key":"10.3233\/JAD-220764_ref13","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1001\/archneur.56.3.303","article-title":"Mild cognitive impairment: Clinical characterization and outcome","volume":"56","author":"Petersen","year":"1999","journal-title":"Arch Neurol"},{"key":"10.3233\/JAD-220764_ref14","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1016\/0076-6879(90)87042-2","article-title":"Synthesis of epoxyeicosatrienoic acids and heteroatom analogs","volume":"187","author":"Falck","year":"1990","journal-title":"Methods Enzymol"},{"key":"10.3233\/JAD-220764_ref15","doi-asserted-by":"crossref","first-page":"3037","DOI":"10.1021\/jm2001376","article-title":"Synthesis and structure-activity relationship studies of urea-containing pyrazoles as dual inhibitors of cyclooxygenase-2 and soluble epoxide hydrolase","volume":"54","author":"Hwang","year":"2011","journal-title":"J Med Chem"},{"key":"10.3233\/JAD-220764_ref16","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","article-title":"STAR: Ultrafast universal RNA-seq aligner","volume":"29","author":"Dobin","year":"2013","journal-title":"Bioinformatics"},{"key":"10.3233\/JAD-220764_ref17","doi-asserted-by":"crossref","first-page":"R106","DOI":"10.1186\/gb-2010-11-10-r106","article-title":"Differential expression analysis for sequence count data","volume":"11","author":"Anders","year":"2010","journal-title":"Genome Biol"},{"key":"10.3233\/JAD-220764_ref18","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/0003-2697(89)90115-2","article-title":"Characterization of glycoproteins and their associated oligosaccharides through the use of endoglycosidases","volume":"180","author":"Maley","year":"1989","journal-title":"Anal Biochem"},{"key":"10.3233\/JAD-220764_ref19","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/0003-2697(88)90089-9","article-title":"Monosaccharide analysis of glycoconjugates by anion exchange chromatography with pulsed amperometric detection","volume":"170","author":"Hardy","year":"1988","journal-title":"Anal Biochem"},{"key":"10.3233\/JAD-220764_ref20","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1046\/j.1365-2362.2002.00994.x","article-title":"Cyclooxygenase-2-positive macrophages infiltrate the Alzheimer\u2019s disease brain and damage the blood-brain barrier","volume":"32","author":"Fiala","year":"2002","journal-title":"Eur J Clin Invest"},{"key":"10.3233\/JAD-220764_ref21","doi-asserted-by":"crossref","first-page":"993","DOI":"10.3233\/JAD-200252","article-title":"Omega-3 fatty acids increase amyloid-beta immunity, energy, and circadian rhythm for cognitive protection of Alzheimer\u2019s disease patients beyond cholinesterase inhibitors","volume":"75","author":"Fiala","year":"2020","journal-title":"J Alzheimers Dis"},{"key":"10.3233\/JAD-220764_ref22","doi-asserted-by":"crossref","first-page":"16458","DOI":"10.1523\/JNEUROSCI.3987-12.2012","article-title":"LRP1 in brain vascular smooth muscle cells mediates local clearance of Alzheimer\u2019s amyloid-beta","volume":"32","author":"Kanekiyo","year":"2012","journal-title":"J Neurosci"},{"key":"10.3233\/JAD-220764_ref23","doi-asserted-by":"crossref","first-page":"151","DOI":"10.3233\/JAD-2012-120319","article-title":"Enhanced brain amyloid-beta clearance by rifampicin and caffeine as a possible protective mechanism against Alzheimer\u2019s disease","volume":"31","author":"Qosa","year":"2012","journal-title":"J Alzheimers Dis"},{"key":"10.3233\/JAD-220764_ref24","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1093\/brain\/awz364","article-title":"Peripherally derived angiotensin converting enzyme-enhanced macrophages alleviate Alzheimer-related disease","volume":"143","author":"Koronyo-Hamaoui","year":"2020","journal-title":"Brain"},{"key":"10.3233\/JAD-220764_ref25","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1038\/nature14432","article-title":"Structural and functional features of central nervous system lymphatic vessels","volume":"523","author":"Louveau","year":"2015","journal-title":"Nature"},{"key":"10.3233\/JAD-220764_ref26","doi-asserted-by":"crossref","first-page":"e2011226118","DOI":"10.1073\/pnas.2011226118","article-title":"NAD(+) supplementation reduces neuroinflammation and cell senescence in a transgenic mouse model of Alzheimer\u2019s disease via cGAS-STING","volume":"118","author":"Hou","year":"2021","journal-title":"Proc Natl Acad Sci U S A"},{"key":"10.3233\/JAD-220764_ref27","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1056\/NEJMoa1211103","article-title":"Variant of TREM2associated with the risk of Alzheimer\u2019s disease","volume":"368","author":"Jonsson","year":"2013","journal-title":"N Engl J Med"},{"key":"10.3233\/JAD-220764_ref28","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1089\/rej.2006.9.77","article-title":"Amyloid-beta immunotherapy for the prevention and treatment of Alzheimer disease: Lessons from mice, monkeys, and humans","volume":"9","author":"Lemere","year":"2006","journal-title":"Rejuvenation Res"},{"key":"10.3233\/JAD-220764_ref29","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1002\/acn3.761","article-title":"Immunotherapy with ponezumab for probable cerebral amyloid angiopathy","volume":"6","author":"Leurent","year":"2019","journal-title":"Ann Clin Transl Neurol"},{"key":"10.3233\/JAD-220764_ref30","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1038\/nature19323","article-title":"The antibody aducanumab reduces A\u03b2 plaques in Alzheimer\u2019s disease","volume":"537","author":"Sevigny","year":"2016","journal-title":"Nature"},{"key":"10.3233\/JAD-220764_ref31","doi-asserted-by":"crossref","first-page":"e12145","DOI":"10.1002\/trc2.12145","article-title":"Cerebral amyloid angiopathy distribution in older people: A cautionary note","volume":"7","author":"Alakbarzade","year":"2021","journal-title":"Alzheimers Dement (N Y)"},{"key":"10.3233\/JAD-220764_ref32","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1159\/000218081","article-title":"Effects of omega-3 fatty acids on inflammatory markers in cerebrospinal fluid and plasma in Alzheimer\u2019s disease: The OmegAD study","volume":"27","author":"Freund-Levi","year":"2009","journal-title":"Dement Geriatr Cogn Disord"},{"key":"10.3233\/JAD-220764_ref33","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.3233\/JAD-170579","article-title":"Immunotherapy of mild cognitive impairment by omega-3 supplementation: Why are amyloid-beta antibodies and omega-3 not working in clinical trials?","volume":"62","author":"Fiala","year":"2018","journal-title":"J Alzheimers Dis"},{"key":"10.3233\/JAD-220764_ref34","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1007\/s12035-011-8200-6","article-title":"Endogenous signaling by omega-3 docosahexaenoic acid-derived mediators sustains homeostatic synaptic and circuitry integrity","volume":"44","author":"Bazan","year":"2011","journal-title":"Mol Neurobiol"},{"key":"10.3233\/JAD-220764_ref35","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/S0163-7827(03)00049-3","article-title":"Epoxyeicosatrienoic acids (EETs): Metabolism and biochemical function","volume":"43","author":"Spector","year":"2004","journal-title":"Prog Lipid Res"},{"key":"10.3233\/JAD-220764_ref36","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.pneurobio.2018.11.001","article-title":"Humble beginnings with big goals: Small molecule soluble epoxide hydrolase inhibitors for treating CNS disorders","volume":"172","author":"Zarriello","year":"2019","journal-title":"Prog Neurobiol"},{"key":"10.3233\/JAD-220764_ref37","doi-asserted-by":"crossref","first-page":"3481","DOI":"10.1194\/jlr.M006007","article-title":"Naturally occurring monoepoxides of eicosapentaenoic acid and docosahexaenoic acid are bioactive antihyperalgesic lipids","volume":"51","author":"Morisseau","year":"2010","journal-title":"J Lipid Res"},{"key":"10.3233\/JAD-220764_ref38","doi-asserted-by":"crossref","first-page":"1402","DOI":"10.1001\/archneur.63.10.1402","article-title":"Omega-3 fatty acid treatment in 174 patients with mild to moderate Alzheimer disease: OmegAD study: A randomized double-blind trial","volume":"63","author":"Freund-Levi","year":"2006","journal-title":"Arch Neurol"},{"key":"10.3233\/JAD-220764_ref39","doi-asserted-by":"crossref","first-page":"1903","DOI":"10.1001\/jama.2010.1510","article-title":"Docosahexaenoic acid supplementation and cognitive decline in Alzheimer disease: A randomized trial","volume":"304","author":"Quinn","year":"2010","journal-title":"JAMA"}],"container-title":["Journal of Alzheimer's Disease"],"original-title":[],"link":[{"URL":"https:\/\/content.iospress.com\/download?id=10.3233\/JAD-220764","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T10:08:02Z","timestamp":1777370882000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/full\/10.3233\/JAD-220764"}},"subtitle":[],"editor":[{"given":"Giulio","family":"Pasinetti","sequence":"additional","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2023,1,3]]},"references-count":39,"journal-issue":{"issue":"1"},"URL":"https:\/\/doi.org\/10.3233\/jad-220764","relation":{},"ISSN":["1387-2877","1875-8908"],"issn-type":[{"value":"1387-2877","type":"print"},{"value":"1875-8908","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,3]]}}}