{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T19:22:46Z","timestamp":1792783366006,"version":"4.5.0"},"reference-count":69,"publisher":"Springer Science and Business Media LLC","issue":"11","license":[{"start":{"date-parts":[[2022,9,9]],"date-time":"2022-09-09T00:00:00Z","timestamp":1662681600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,9,9]],"date-time":"2022-09-09T00:00:00Z","timestamp":1662681600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"ANR","award":["ANR-10-IAIHU-06"],"award-info":[{"award-number":["ANR-10-IAIHU-06"]}]},{"name":"ANR","award":["ANR-18-COEN-0002 COEN4024"],"award-info":[{"award-number":["ANR-18-COEN-0002 COEN4024"]}]},{"DOI":"10.13039\/501100013945","name":"Institut de Recherches Servier","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100013945","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004359","name":"Swedish Research Council","doi-asserted-by":"crossref","award":["#2018-02532"],"award-info":[{"award-number":["#2018-02532"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100004359","name":"Swedish Research Council","doi-asserted-by":"crossref","award":["#2017-00915"],"award-info":[{"award-number":["#2017-00915"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","award":["#681712"],"award-info":[{"award-number":["#681712"]}],"id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Swedish State Support for Clinical Research","award":["#ALFGBG-720931"],"award-info":[{"award-number":["#ALFGBG-720931"]}]},{"DOI":"10.13039\/100002565","name":"Alzheimer Drug Discovery Foundation","doi-asserted-by":"crossref","award":["#201809-2016862"],"award-info":[{"award-number":["#201809-2016862"]}],"id":[{"id":"10.13039\/100002565","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100002565","name":"Alzheimer Drug Discovery Foundation","doi-asserted-by":"crossref","award":["#RDAPB-201809-2016615"],"award-info":[{"award-number":["#RDAPB-201809-2016615"]}],"id":[{"id":"10.13039\/100002565","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Swedish Alzheimer Foundation","award":["#AF-742881"],"award-info":[{"award-number":["#AF-742881"]}]},{"name":"Hj\u00e4rnfonden, Sweden","award":["#FO2017-0243"],"award-info":[{"award-number":["#FO2017-0243"]}]},{"name":"ALF-agreement","award":["#ALFGBG-715986"],"award-info":[{"award-number":["#ALFGBG-715986"]}]},{"DOI":"10.13039\/100013278","name":"EU Joint Programme \u2013 Neurodegenerative Disease Research","doi-asserted-by":"publisher","award":["JPND2019-466-236"],"award-info":[{"award-number":["JPND2019-466-236"]}],"id":[{"id":"10.13039\/100013278","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000056","name":"National Institute of Nursing Research","doi-asserted-by":"publisher","award":["#1R01AG068398-01"],"award-info":[{"award-number":["#1R01AG068398-01"]}],"id":[{"id":"10.13039\/100000056","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000957","name":"Alzheimer's Association","doi-asserted-by":"publisher","award":["2021 Zenith Award"],"award-info":[{"award-number":["2021 Zenith Award"]}],"id":[{"id":"10.13039\/100000957","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Mol Neurobiol"],"published-print":{"date-parts":[[2022,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Excess brain cholesterol is strongly implicated in the pathogenesis of Alzheimer\u2019s disease (AD). Here we evaluated how the presence of a cholesterol-binding site (CBS) in the transmembrane and juxtamembrane regions of the amyloid precursor protein (APP) regulates its processing. We generated nine point mutations in the\n                    <jats:italic>APP<\/jats:italic>\n                    gene, changing the charge and\/or hydrophobicity of the amino-acids which were previously shown as part of the CBS. Most mutations triggered a reduction of amyloid-\u03b2 peptides A\u03b240 and A\u03b242 secretion from transiently transfected HEK293T cells. Only the mutations at position 28 of A\u03b2 in the APP sequence resulted in a concomitant significant increase in the production of shorter A\u03b2 peptides. Mass spectrometry (MS) confirmed the predominance of A\u03b2x-33 and A\u03b2x-34 with the APP\n                    <jats:sup>K28A<\/jats:sup>\n                    mutant. The enzymatic activity of \u03b1-, \u03b2-, and \u03b3-secretases remained unchanged in cells expressing all mutants. Similarly, subcellular localization of the mutants in early endosomes did not differ from the APP\n                    <jats:sup>WT<\/jats:sup>\n                    protein. A transient increase of plasma membrane cholesterol enhanced the production of A\u03b240 and A\u03b242 by APP\n                    <jats:sup>WT<\/jats:sup>\n                    , an effect absent in APP\n                    <jats:sup>K28A<\/jats:sup>\n                    mutant. Finally, WT but not CBS mutant A\u03b2 derived peptides bound to cholesterol-rich exosomes. Collectively, the present data revealed a major role of juxtamembrane amino acids of the APP CBS in modulating the production of toxic A\u03b2 species. More generally, they underpin the role of cholesterol in the pathophysiology of AD.\n                  <\/jats:p>","DOI":"10.1007\/s12035-022-03025-9","type":"journal-article","created":{"date-parts":[[2022,9,8]],"date-time":"2022-09-08T20:02:36Z","timestamp":1662667356000},"page":"7056-7073","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Specific Mutations in the Cholesterol-Binding Site of APP Alter Its Processing and Favor the Production of Shorter, Less Toxic A\u03b2 Peptides"],"prefix":"10.1007","volume":"59","author":[{"given":"Linda","family":"Hanbouch","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B\u00e9atrice","family":"Schaack","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amal","family":"Kasri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ga\u00eblle","family":"Fontaine","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleni","family":"Gkanatsiou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gunnar","family":"Brinkmalm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Camporesi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik","family":"Portelius","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaj","family":"Blennow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gilles","family":"Mourier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"Gilles","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark J.","family":"Millan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Marquer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henrik","family":"Zetterberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lydie","family":"Boussicault","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2462-7150","authenticated-orcid":false,"given":"Marie-Claude","family":"Potier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,9,9]]},"reference":[{"key":"3025_CR1","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1007\/s00401-009-0532-1","volume":"118","author":"C Duyckaerts","year":"2009","unstructured":"Duyckaerts C, Delatour B, Potier MC (2009) Classification and basic pathology of Alzheimer disease. Acta Neuropathol 118:5\u201336","journal-title":"Acta Neuropathol"},{"key":"3025_CR2","doi-asserted-by":"publisher","first-page":"595","DOI":"10.15252\/emmm.201606210","volume":"8","author":"DJ Selkoe","year":"2016","unstructured":"Selkoe DJ, Hardy J (2016) The amyloid hypothesis of Alzheimer\u2019s disease at 25 years. EMBO Mol Med 8:595\u2013608","journal-title":"EMBO Mol Med"},{"key":"3025_CR3","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1146\/annurev-cellbio-100109-104117","volume":"26","author":"B De Strooper","year":"2010","unstructured":"De Strooper B, Annaert W (2010) Novel research horizons for presenilins and gamma-secretases in cell biology and disease. Annu Rev Cell Dev Biol 26:235\u2013260","journal-title":"Annu Rev Cell Dev Biol"},{"key":"3025_CR4","doi-asserted-by":"publisher","first-page":"841","DOI":"10.1016\/S1474-4422(05)70248-9","volume":"4","author":"LA Shobab","year":"2005","unstructured":"Shobab LA, Hsiung GY, Feldman HH (2005) Cholesterol in Alzheimer\u2019s disease. Lancet Neurol 4:841\u2013852","journal-title":"Lancet Neurol"},{"key":"3025_CR5","doi-asserted-by":"publisher","first-page":"1977","DOI":"10.1073\/pnas.90.5.1977","volume":"90","author":"WJ Strittmatter","year":"1993","unstructured":"Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS, Roses AD (1993) Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci U S A 90:1977\u20131981","journal-title":"Proc Natl Acad Sci U S A"},{"key":"3025_CR6","doi-asserted-by":"publisher","first-page":"2070","DOI":"10.1073\/pnas.0305799101","volume":"101","author":"RG Cutler","year":"2004","unstructured":"Cutler RG, Kelly J, Storie K, Pedersen WA, Tammara A, Hatanpaa K, Troncoso JC, Mattson MP (2004) Involvement of oxidative stress-induced abnormalities in ceramide and cholesterol metabolism in brain aging and Alzheimer\u2019s disease. Proc Natl Acad Sci U S A 101:2070\u20132075","journal-title":"Proc Natl Acad Sci U S A"},{"key":"3025_CR7","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1038\/nrn3012","volume":"12","author":"G Di Paolo","year":"2011","unstructured":"Di Paolo G, Kim TW (2011) Linking lipids to Alzheimer\u2019s disease: cholesterol and beyond. Nat Rev Neurosci 12:284\u2013296","journal-title":"Nat Rev Neurosci"},{"key":"3025_CR8","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1007\/s00401-012-1041-1","volume":"125","author":"AN Lazar","year":"2012","unstructured":"Lazar AN, Bich C, Panchal M, Desbenoit N, Petit VW, Touboul D, Dauphinot L, Marquer C, Laprevote O, Brunelle A, Duyckaerts C (2012) Time-of-flight secondary ion mass spectrometry (TOF-SIMS) imaging reveals cholesterol overload in the cerebral cortex of Alzheimer disease patients. Acta Neuropathol 125:133\u2013144","journal-title":"Acta Neuropathol"},{"key":"3025_CR9","doi-asserted-by":"publisher","first-page":"598","DOI":"10.1194\/jlr.M001859","volume":"51","author":"M Panchal","year":"2010","unstructured":"Panchal M, Loeper J, Cossec JC, Perruchini C, Lazar A, Pompon D, Duyckaerts C (2010) Enrichment of cholesterol in microdissected Alzheimer\u2019s disease senile plaques as assessed by mass spectrometry. J Lipid Res 51:598\u2013605","journal-title":"J Lipid Res"},{"key":"3025_CR10","doi-asserted-by":"publisher","first-page":"422","DOI":"10.1016\/j.nbd.2007.10.005","volume":"29","author":"H Xiong","year":"2008","unstructured":"Xiong H, Callaghan D, Jones A, Walker DG, Lue LF, Beach TG, Sue LI, Woulfe J, Xu H, Stanimirovic DB, Zhang W (2008) Cholesterol retention in Alzheimer\u2019s brain is responsible for high beta- and gamma-secretase activities and A beta production. Neurobiol Dis 29:422\u2013437","journal-title":"Neurobiol Dis"},{"key":"3025_CR11","doi-asserted-by":"publisher","first-page":"11735","DOI":"10.1073\/pnas.1635130100","volume":"100","author":"JM Cordy","year":"2003","unstructured":"Cordy JM, Hussain I, Dingwall C, Hooper NM, Turner AJ (2003) Exclusively targeting beta-secretase to lipid rafts by GPI-anchor addition up-regulates beta-site processing of the amyloid precursor protein. Proc Natl Acad Sci U S A 100:11735\u201311740","journal-title":"Proc Natl Acad Sci U S A"},{"key":"3025_CR12","doi-asserted-by":"publisher","first-page":"6460","DOI":"10.1073\/pnas.95.11.6460","volume":"95","author":"M Simons","year":"1998","unstructured":"Simons M, Keller P, De Strooper B, Beyreuther K, Dotti CG, Simons K (1998) Cholesterol depletion inhibits the generation of beta-amyloid in hippocampal neurons. Proc Natl Acad Sci U S A 95:6460\u20136464","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"8","key":"3025_CR13","doi-asserted-by":"publisher","first-page":"839","DOI":"10.1016\/j.bbalip.2010.03.010","volume":"1801","author":"JC Cossec","year":"2010","unstructured":"Cossec JC, Marquer C, Panchal M, Lazar AN, Duyckaerts C, Potier MC (2010) Cholesterol changes in Alzheimer\u2019s disease: methods of analysis and impact on the formation of enlarged endosomes. Biochim Biophys Acta 1801(8):839\u2013845","journal-title":"Biochim Biophys Acta"},{"key":"3025_CR14","doi-asserted-by":"publisher","first-page":"846","DOI":"10.1016\/j.bbalip.2010.05.010","volume":"1801","author":"JC Cossec","year":"2010","unstructured":"Cossec JC, Simon A, Marquer C, Moldrich RX, Leterrier C, Rossier J, Duyckaerts C, Lenkei Z, Potier MC (2010) Clathrin-dependent APP endocytosis and Abeta secretion are highly sensitive to the level of plasma membrane cholesterol. Biochim Biophys Acta 1801:846\u2013852","journal-title":"Biochim Biophys Acta"},{"key":"3025_CR15","doi-asserted-by":"publisher","first-page":"1295","DOI":"10.1096\/fj.10-168633","volume":"25","author":"C Marquer","year":"2011","unstructured":"Marquer C, Devauges V, Cossec JC, Liot G, Lecart S, Saudou F, Duyckaerts C, Leveque-Fort S, Potier MC (2011) Local cholesterol increase triggers amyloid precursor protein-Bace1 clustering in lipid rafts and rapid endocytosis. FASEB J 25:1295\u20131305","journal-title":"FASEB J"},{"key":"3025_CR16","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1186\/1750-1326-9-60","volume":"9","author":"C Marquer","year":"2014","unstructured":"Marquer C, Laine J, Dauphinot L, Hanbouch L, Lemercier-Neuillet C, Pierrot N, Bossers K, Le M, Corlier F, Benstaali C, Saudou F, Thinakaran G, Cartier N, Octave JN, Duyckaerts C, Potier MC (2014) Increasing membrane cholesterol of neurons in culture recapitulates Alzheimer\u2019s disease early phenotypes. Mol Neurodegener 9:60","journal-title":"Mol Neurodegener"},{"key":"3025_CR17","doi-asserted-by":"publisher","first-page":"11302","DOI":"10.1074\/jbc.M801520200","volume":"283","author":"MO Grimm","year":"2008","unstructured":"Grimm MO, Grimm HS, Tomic I, Beyreuther K, Hartmann T, Bergmann C (2008) Independent inhibition of Alzheimer disease beta- and gamma-secretase cleavage by lowered cholesterol levels. J Biol Chem 283:11302\u201311311","journal-title":"J Biol Chem"},{"key":"3025_CR18","doi-asserted-by":"publisher","first-page":"22529","DOI":"10.1074\/jbc.M801925200","volume":"283","author":"P Osenkowski","year":"2008","unstructured":"Osenkowski P, Ye W, Wang R, Wolfe MS, Selkoe DJ (2008) Direct and potent regulation of gamma-secretase by its lipid microenvironment. J Biol Chem 283:22529\u201322540","journal-title":"J Biol Chem"},{"key":"3025_CR19","doi-asserted-by":"publisher","first-page":"608","DOI":"10.1002\/emmm.201202215","volume":"5","author":"N Pierrot","year":"2013","unstructured":"Pierrot N, Tyteca D, D\u2019Auria L, Dewachter I, Gailly P, Hendrickx A, Tasiaux B, Haylani LE, Muls N, N\u2019Kuli F, Laquerriere A, Demoulin JB, Campion D, Brion JP, Courtoy PJ, Kienlen-Campard P, Octave JN (2013) Amyloid precursor protein controls cholesterol turnover needed for neuronal activity. EMBO Mol Med 5:608\u2013625","journal-title":"EMBO Mol Med"},{"key":"3025_CR20","doi-asserted-by":"publisher","first-page":"4489","DOI":"10.1021\/bi500373k","volume":"53","author":"C Di Scala","year":"2014","unstructured":"Di Scala C, Chahinian H, Yahi N, Garmy N, Fantini J (2014) Interaction of Alzheimer\u2019s beta-amyloid peptides with cholesterol: mechanistic insights into amyloid pore formation. Biochemistry 53:4489\u20134502","journal-title":"Biochemistry"},{"key":"3025_CR21","doi-asserted-by":"publisher","first-page":"120","DOI":"10.3389\/fphys.2013.00120","volume":"4","author":"J Fantini","year":"2013","unstructured":"Fantini J, Yahi N, Garmy N (2013) Cholesterol accelerates the binding of Alzheimer\u2019s beta-amyloid peptide to ganglioside GM1 through a universal hydrogen-bond-dependent sterol tuning of glycolipid conformation. Front Physiol 4:120","journal-title":"Front Physiol"},{"key":"3025_CR22","doi-asserted-by":"publisher","first-page":"1168","DOI":"10.1126\/science.1219988","volume":"336","author":"PJ Barrett","year":"2012","unstructured":"Barrett PJ, Song Y, Van Horn WD, Hustedt EJ, Schafer JM, Hadziselimovic A, Beel AJ, Sanders CR (2012) The amyloid precursor protein has a flexible transmembrane domain and binds cholesterol. Science 336:1168\u20131171","journal-title":"Science"},{"key":"3025_CR23","doi-asserted-by":"publisher","first-page":"9428","DOI":"10.1021\/bi800993c","volume":"47","author":"AJ Beel","year":"2008","unstructured":"Beel AJ, Mobley CK, Kim HJ, Tian F, Hadziselimovic A, Jap B, Prestegard JH, Sanders CR (2008) Structural studies of the transmembrane C-terminal domain of the amyloid precursor protein (APP): does APP function as a cholesterol sensor? Biochemistry 47:9428\u20139446","journal-title":"Biochemistry"},{"issue":"8","key":"3025_CR24","doi-asserted-by":"publisher","first-page":"975","DOI":"10.1016\/j.bbalip.2010.03.008","volume":"1801","author":"AJ Beel","year":"2012","unstructured":"Beel AJ, Sakakura M, Barrett PJ, Sanders CR (2012) Direct binding of cholesterol to the amyloid precursor protein: an important interaction in lipid-Alzheimer\u2019s disease relationships? Biochim Biophys Acta 1801(8):975\u2013982","journal-title":"Biochim Biophys Acta"},{"key":"3025_CR25","doi-asserted-by":"publisher","first-page":"784","DOI":"10.1021\/acs.jpclett.5b00197","volume":"6","author":"L Nierzwicki","year":"2015","unstructured":"Nierzwicki L, Czub J (2015) Specific binding of cholesterol to the amyloid precursor protein: structure of the complex and driving forces characterized in molecular detail. J Phys Chem Lett 6:784\u2013790","journal-title":"J Phys Chem Lett"},{"key":"3025_CR26","doi-asserted-by":"publisher","first-page":"101887","DOI":"10.1016\/j.isci.2020.101887","volume":"23","author":"F Perrin","year":"2020","unstructured":"Perrin F, Papadopoulos N, Suelves N, Opsomer R, Vadukul DM, Vrancx C, Smith SO, Vertommen D, Kienlen-Campard P, Constantinescu SN (2020) Dimeric transmembrane orientations of APP\/C99 regulate gamma-secretase processing line impacting signaling and oligomerization. iScience 23:101887","journal-title":"iScience"},{"key":"3025_CR27","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1084\/jem.20170600","volume":"215","author":"BD Moore","year":"2018","unstructured":"Moore BD, Martin J, de Mena L, Sanchez J, Cruz PE, Ceballos-Diaz C, Ladd TB, Ran Y, Levites Y, Kukar TL, Kurian JJ, McKenna R, Koo EH, Borchelt DR, Janus C, Rincon-Limas D, Fernandez-Funez P, Golde TE (2018) Short Abeta peptides attenuate Abeta42 toxicity in vivo. J Exp Med 215:283\u2013301","journal-title":"J Exp Med"},{"key":"3025_CR28","doi-asserted-by":"publisher","first-page":"4088","DOI":"10.1016\/j.febslet.2012.10.022","volume":"586","author":"A Vandersteen","year":"2012","unstructured":"Vandersteen A, Hubin E, Sarroukh R, De Baets G, Schymkowitz J, Rousseau F, Subramaniam V, Raussens V, Wenschuh H, Wildemann D, Broersen K (2012) A comparative analysis of the aggregation behavior of amyloid-beta peptide variants. FEBS Lett 586:4088\u20134093","journal-title":"FEBS Lett"},{"key":"3025_CR29","doi-asserted-by":"publisher","first-page":"1016","DOI":"10.1038\/nm0997-1016","volume":"3","author":"T Hartmann","year":"1997","unstructured":"Hartmann T, Bieger SC, Bruhl B, Tienari PJ, Ida N, Allsop D, Roberts GW, Masters CL, Dotti CG, Unsicker K, Beyreuther K (1997) Distinct sites of intracellular production for Alzheimer\u2019s disease A beta40\/42 amyloid peptides. Nat Med 3:1016\u20131020","journal-title":"Nat Med"},{"key":"3025_CR30","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.722581","volume":"12","author":"M Abdullah","year":"2021","unstructured":"Abdullah M, Nakamura T, Ferdous T, Gao Y, Chen Y, Zou K, Michikawa M (2021) Cholesterol regulates exosome release in cultured astrocytes. Front Immunol 12:722581","journal-title":"Front Immunol"},{"key":"3025_CR31","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1194\/jlr.R084343","volume":"60","author":"T Skotland","year":"2019","unstructured":"Skotland T, Hessvik NP, Sandvig K, Llorente A (2019) Exosomal lipid composition and the role of ether lipids and phosphoinositides in exosome biology. J Lipid Res 60:9\u201318","journal-title":"J Lipid Res"},{"key":"3025_CR32","doi-asserted-by":"publisher","first-page":"7733","DOI":"10.1074\/jbc.M707142200","volume":"283","author":"P Kienlen-Campard","year":"2008","unstructured":"Kienlen-Campard P, Tasiaux B, Van Hees J, Li M, Huysseune S, Sato T, Fei JZ, Aimoto S, Courtoy PJ, Smith SO, Constantinescu SN, Octave JN (2008) Amyloidogenic processing but not amyloid precursor protein (APP) intracellular C-terminal domain production requires a precisely oriented APP dimer assembled by transmembrane GXXXG motifs. J Biol Chem 283:7733\u20137744","journal-title":"J Biol Chem"},{"key":"3025_CR33","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2021.100393","volume":"296","author":"L Liu","year":"2021","unstructured":"Liu L, Lauro BM, Wolfe MS, Selkoe DJ (2021) Hydrophilic loop 1 of Presenilin-1 and the APP GxxxG transmembrane motif regulate gamma-secretase function in generating Alzheimer-causing Abeta peptides. J Biol Chem 296:100393","journal-title":"J Biol Chem"},{"key":"3025_CR34","doi-asserted-by":"publisher","first-page":"3535","DOI":"10.1021\/acs.jpclett.6b01624","volume":"7","author":"A Panahi","year":"2016","unstructured":"Panahi A, Bandara A, Pantelopulos GA, Dominguez L, Straub JE (2016) Specific binding of cholesterol to C99 domain of amyloid precursor protein depends critically on charge state of protein. J Phys Chem Lett 7:3535\u20133541","journal-title":"J Phys Chem Lett"},{"key":"3025_CR35","doi-asserted-by":"publisher","first-page":"987","DOI":"10.1001\/archneurol.2010.178","volume":"67","author":"O Bugiani","year":"2010","unstructured":"Bugiani O, Giaccone G, Rossi G, Mangieri M, Capobianco R, Morbin M, Mazzoleni G, Cupidi C, Marcon G, Giovagnoli A, Bizzi A, Di Fede G, Puoti G, Carella F, Salmaggi A, Romorini A, Patruno GM, Magoni M, Padovani A, Tagliavini F (2010) Hereditary cerebral hemorrhage with amyloidosis associated with the E693K mutation of APP. Arch Neurol 67:987\u2013995","journal-title":"Arch Neurol"},{"key":"3025_CR36","doi-asserted-by":"publisher","first-page":"27110","DOI":"10.1016\/S0021-9258(19)61486-9","volume":"275","author":"L Miravalle","year":"2000","unstructured":"Miravalle L, Tokuda T, Chiarle R, Giaccone G, Bugiani O, Tagliavini F, Frangione B, Ghiso J (2000) Substitutions at codon 22 of Alzheimer\u2019s abeta peptide induce diverse conformational changes and apoptotic effects in human cerebral endothelial cells. J Biol Chem 275:27110\u201327116","journal-title":"J Biol Chem"},{"key":"3025_CR37","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1002\/ana.21321","volume":"63","author":"T Tomiyama","year":"2008","unstructured":"Tomiyama T, Nagata T, Shimada H, Teraoka R, Fukushima A, Kanemitsu H, Takuma H, Kuwano R, Imagawa M, Ataka S, Wada Y, Yoshioka E, Nishizaki T, Watanabe Y, Mori H (2008) A new amyloid beta variant favoring oligomerization in Alzheimer\u2019s-type dementia. Ann Neurol 63:377\u2013387","journal-title":"Ann Neurol"},{"key":"3025_CR38","doi-asserted-by":"publisher","first-page":"887","DOI":"10.1038\/nn0901-887","volume":"4","author":"C Nilsberth","year":"2001","unstructured":"Nilsberth C, Westlind-Danielsson A, Eckman CB, Condron MM, Axelman K, Forsell C, Stenh C, Luthman J, Teplow DB, Younkin SG, Naslund J, Lannfelt L (2001) The \u2018Arctic\u2019 APP mutation (E693G) causes Alzheimer\u2019s disease by enhanced Abeta protofibril formation. Nat Neurosci 4:887\u2013893","journal-title":"Nat Neurosci"},{"issue":"363\u2013375","key":"3025_CR39","volume":"24","author":"R van der Kant","year":"2019","unstructured":"van der Kant R, Langness VF, Herrera CM, Williams DA, Fong LK, Leestemaker Y, Steenvoorden E, Rynearson KD, Brouwers JF, Helms JB, Ovaa H, Giera M, Wagner SL, Bang AG, Goldstein LSB (2019) Cholesterol metabolism is a druggable axis that independently regulates tau and amyloid-beta in iPSC-derived Alzheimer\u2019s disease neurons. Cell Stem Cell 24(363\u2013375):e369","journal-title":"Cell Stem Cell"},{"key":"3025_CR40","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.bpc.2015.07.010","volume":"208","author":"MC Nicastro","year":"2016","unstructured":"Nicastro MC, Spigolon D, Librizzi F, Moran O, Ortore MG, Bulone D, Biagio PL, Carrotta R (2016) Amyloid beta-peptide insertion in liposomes containing GM1-cholesterol domains. Biophys Chem 208:9\u201316","journal-title":"Biophys Chem"},{"key":"3025_CR41","doi-asserted-by":"publisher","first-page":"750","DOI":"10.1111\/tra.12586","volume":"19","author":"TL Steck","year":"2018","unstructured":"Steck TL, Lange Y (2018) Transverse distribution of plasma membrane bilayer cholesterol: picking sides. Traffic 19:750\u2013760","journal-title":"Traffic"},{"key":"3025_CR42","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1016\/j.chemphyslip.2015.08.009","volume":"194","author":"M Murate","year":"2016","unstructured":"Murate M, Kobayashi T (2016) Revisiting transbilayer distribution of lipids in the plasma membrane. Chem Phys Lipids 194:58\u201371","journal-title":"Chem Phys Lipids"},{"key":"3025_CR43","doi-asserted-by":"publisher","first-page":"5627","DOI":"10.1038\/s41598-019-41903-w","volume":"9","author":"T Rivel","year":"2019","unstructured":"Rivel T, Ramseyer C, Yesylevskyy S (2019) The asymmetry of plasma membranes and their cholesterol content influence the uptake of cisplatin. Sci Rep 9:5627","journal-title":"Sci Rep"},{"key":"3025_CR44","doi-asserted-by":"publisher","first-page":"35350","DOI":"10.1074\/jbc.M702739200","volume":"282","author":"Z Ren","year":"2007","unstructured":"Ren Z, Schenk D, Basi GS, Shapiro IP (2007) Amyloid beta-protein precursor juxtamembrane domain regulates specificity of gamma-secretase-dependent cleavages. J Biol Chem 282:35350\u201335360","journal-title":"J Biol Chem"},{"key":"3025_CR45","doi-asserted-by":"publisher","first-page":"39804","DOI":"10.1074\/jbc.M111.274696","volume":"286","author":"TL Kukar","year":"2011","unstructured":"Kukar TL, Ladd TB, Robertson P, Pintchovski SA, Moore B, Bann MA, Ren Z, Jansen-West K, Malphrus K, Eggert S, Maruyama H, Cottrell BA, Das P, Basi GS, Koo EH, Golde TE (2011) Lysine 624 of the amyloid precursor protein (APP) is a critical determinant of amyloid beta peptide length: support for a sequential model of gamma-secretase intramembrane proteolysis and regulation by the amyloid beta precursor protein (APP) juxtamembraneregion. J Biol Chem 286:39804\u201339812","journal-title":"J Biol Chem"},{"key":"3025_CR46","doi-asserted-by":"publisher","first-page":"610","DOI":"10.1111\/jnc.12129","volume":"125","author":"S Ousson","year":"2013","unstructured":"Ousson S, Saric A, Baguet A, Losberger C, Genoud S, Vilbois F, Permanne B, Hussain I, Beher D (2013) Substrate determinants in the C99 juxtamembranedomains differentially affect gamma-secretase cleavage specificity and modulator pharmacology. J Neurochem 125:610\u2013619","journal-title":"J Neurochem"},{"key":"3025_CR47","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2021.100281","volume":"296","author":"S Devkota","year":"2021","unstructured":"Devkota S, Williams TD, Wolfe MS (2021) Familial Alzheimer\u2019s disease mutations in amyloid protein precursor alter proteolysis by gamma-secretase to increase amyloid beta-peptides of >\/=45 residues. J Biol Chem 296:100281","journal-title":"J Biol Chem"},{"key":"3025_CR48","doi-asserted-by":"crossref","unstructured":"Zhou R, Yang G, Guo X, Zhou Q, Lei J, Shi Y (2019) Recognition of the amyloid precursor protein by human gamma-secretase. Science\u00a0363(6428):eaaw0930","DOI":"10.1126\/science.aaw0930"},{"key":"3025_CR49","doi-asserted-by":"publisher","first-page":"815","DOI":"10.1016\/j.jmb.2008.04.028","volume":"379","author":"B Tarus","year":"2008","unstructured":"Tarus B, Straub JE, Thirumalai D (2008) Structures and free-energy landscapes of the wild type and mutants of the Abeta(21\u201330) peptide are determined by an interplay between intrapeptide electrostatic and hydrophobic interactions. J Mol Biol 379:815\u2013829","journal-title":"J Mol Biol"},{"key":"3025_CR50","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1016\/j.npep.2011.09.001","volume":"45","author":"D Sambasivam","year":"2011","unstructured":"Sambasivam D, Sivanesan S, Ashok BS, Rajadas J (2011) Structural preferences of Abeta fragments in different micellar environments. Neuropeptides 45:369\u2013376","journal-title":"Neuropeptides"},{"key":"3025_CR51","doi-asserted-by":"publisher","first-page":"708","DOI":"10.1080\/07391102.2019.1586587","volume":"38","author":"S Shuaib","year":"2020","unstructured":"Shuaib S, Saini RK, Goyal D, Goyal B (2020) Impact of K16A and K28A mutation on the structure and dynamics of amyloid-beta42 peptide in Alzheimer\u2019s disease: key insights from molecular dynamics simulations. J Biomol Struct Dyn 38:708\u2013721","journal-title":"J Biomol Struct Dyn"},{"key":"3025_CR52","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1126\/science.abm7285","volume":"375","author":"Y Yang","year":"2022","unstructured":"Yang Y, Arseni D, Zhang W, Huang M, Lovestam S, Schweighauser M, Kotecha A, Murzin AG, Peak-Chew SY, Macdonald J, Lavenir I, Garringer HJ, Gelpi E, Newell KL, Kovacs GG, Vidal R, Ghetti B, Ryskeldi-Falcon B, Scheres SHW, Goedert M (2022) Cryo-EM structures of amyloid-beta 42 filaments from human brains. Science 375:167\u2013172","journal-title":"Science"},{"key":"3025_CR53","doi-asserted-by":"publisher","first-page":"5531","DOI":"10.1074\/jbc.M211485200","volume":"278","author":"R Fluhrer","year":"2003","unstructured":"Fluhrer R, Multhaup G, Schlicksupp A, Okochi M, Takeda M, Lammich S, Willem M, Westmeyer G, Bode W, Walter J, Haass C (2003) Identification of a beta-secretase activity, which truncates amyloid beta-peptide after its presenilin-dependent generation. J Biol Chem 278:5531\u20135538","journal-title":"J Biol Chem"},{"key":"3025_CR54","doi-asserted-by":"publisher","first-page":"21286","DOI":"10.1074\/jbc.M209859200","volume":"278","author":"XP Shi","year":"2003","unstructured":"Shi XP, Tugusheva K, Bruce JE, Lucka A, Wu GX, Chen-Dodson E, Price E, Li Y, Xu M, Huang Q, Sardana MK, Hazuda DJ (2003) Beta-secretase cleavage at amino acid residue 34 in the amyloid beta peptide is dependent upon gamma-secretase activity. J Biol Chem 278:21286\u201321294","journal-title":"J Biol Chem"},{"key":"3025_CR55","doi-asserted-by":"publisher","first-page":"1570","DOI":"10.1016\/j.neurobiolaging.2014.01.011","volume":"35","author":"C Caillava","year":"2014","unstructured":"Caillava C, Ranaldi S, Lauritzen I, Bauer C, Fareh J, Abraham JD, Checler F (2014) Study on Abeta34 biology and detection in transgenic mice brains. Neurobiol Aging 35:1570\u20131581","journal-title":"Neurobiol Aging"},{"key":"3025_CR56","doi-asserted-by":"publisher","first-page":"463","DOI":"10.3233\/JAD-181191","volume":"69","author":"SC Akerman","year":"2019","unstructured":"Akerman SC, Hossain S, Shobo A, Zhong Y, Jourdain R, Hancock MA, George K, Breton L, Multhaup G (2019) Neurodegenerative disease-related proteins within the epidermal layer of the human skin. J Alzheimers Dis 69:463\u2013478","journal-title":"J Alzheimers Dis"},{"key":"3025_CR57","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1186\/s40478-019-0846-8","volume":"7","author":"T Kirabali","year":"2019","unstructured":"Kirabali T, Rigotti S, Siccoli A, Liebsch F, Shobo A, Hock C, Nitsch RM, Multhaup G, Kulic L (2019) The amyloid-beta degradation intermediate Abeta34 is pericyte-associated and reduced in brain capillaries of patients with Alzheimer\u2019s disease. Acta Neuropathol Commun 7:194","journal-title":"Acta Neuropathol Commun"},{"key":"3025_CR58","doi-asserted-by":"publisher","first-page":"2240","DOI":"10.1038\/s41467-019-10152-w","volume":"10","author":"F Liebsch","year":"2019","unstructured":"Liebsch F, Kulic L, Teunissen C, Shobo A, Ulku I, Engelschalt V, Hancock MA, van der Flier WM, Kunach P, Rosa-Neto P, Scheltens P, Poirier J, Saftig P, Bateman RJ, Breitner J, Hock C, Multhaup G (2019) Abeta34 is a BACE1-derived degradation intermediate associated with amyloid clearance and Alzheimer\u2019s disease progression. Nat Commun 10:2240","journal-title":"Nat Commun"},{"key":"3025_CR59","doi-asserted-by":"publisher","first-page":"15078","DOI":"10.1074\/jbc.M114.610931","volume":"290","author":"M Hernandez-Guillamon","year":"2015","unstructured":"Hernandez-Guillamon M, Mawhirt S, Blais S, Montaner J, Neubert TA, Rostagno A, Ghiso J (2015) Sequential amyloid-beta degradation by the matrix metalloproteases MMP-2 and MMP-9. J Biol Chem 290:15078\u201315091","journal-title":"J Biol Chem"},{"key":"3025_CR60","doi-asserted-by":"publisher","first-page":"756","DOI":"10.1111\/jnc.12675","volume":"129","author":"E Dawkins","year":"2014","unstructured":"Dawkins E, Small DH (2014) Insights into the physiological function of the beta-amyloid precursor protein: beyond Alzheimer\u2019s disease. J Neurochem 129:756\u2013769","journal-title":"J Neurochem"},{"key":"3025_CR61","doi-asserted-by":"publisher","first-page":"1023","DOI":"10.1126\/science.1252884","volume":"344","author":"BG Wilhelm","year":"2014","unstructured":"Wilhelm BG, Mandad S, Truckenbrodt S, Krohnert K, Schafer C, Rammner B, Koo SJ, Classen GA, Krauss M, Haucke V, Urlaub H, Rizzoli SO (2014) Composition of isolated synaptic boutons reveals the amounts of vesicle trafficking proteins. Science 344:1023\u20131028","journal-title":"Science"},{"issue":"2","key":"3025_CR62","doi-asserted-by":"publisher","first-page":"673","DOI":"10.1111\/ejn.14949","volume":"53","author":"NP Samant","year":"2020","unstructured":"Samant NP, Gupta GL (2020) Novel therapeutic strategies for Alzheimer\u2019s disease targeting brain cholesterol homeostasis. Eur J Neurosci 53(2):673\u2013686","journal-title":"Eur J Neurosci"},{"key":"3025_CR63","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1038\/mt.2009.175","volume":"18","author":"E Hudry","year":"2010","unstructured":"Hudry E, Van Dam D, Kulik W, De Deyn PP, Stet FS, Ahouansou O, Benraiss A, Delacourte A, Bougneres P, Aubourg P, Cartier N (2010) Adeno-associated virus gene therapy with cholesterol 24-hydroxylase reduces the amyloid pathology before or after the onset of amyloid plaques in mouse models of Alzheimer\u2019s disease. Mol Ther 18:44\u201353","journal-title":"Mol Ther"},{"issue":"9","key":"3025_CR64","doi-asserted-by":"publisher","first-page":"295","DOI":"10.3390\/biomedicines8090295","volume":"8","author":"AJ Lopez-Gambero","year":"2020","unstructured":"Lopez-Gambero AJ, Sanjuan C, Serrano-Castro PJ, Suarez J, Rodriguez de Fonseca F (2020) The biomedical uses of inositols: a nutraceutical approach to metabolic dysfunction in aging and neurodegenerative diseases. Biomedicines 8(9):295","journal-title":"Biomedicines"},{"key":"3025_CR65","doi-asserted-by":"publisher","first-page":"451","DOI":"10.1021\/cn200133x","volume":"3","author":"S Sinha","year":"2012","unstructured":"Sinha S, Du Z, Maiti P, Klarner FG, Schrader T, Wang C, Bitan G (2012) Comparison of three amyloid assembly inhibitors: the sugar scyllo-inositol, the polyphenol epigallocatechin gallate, and the molecular tweezer CLR01. ACS Chem Neurosci 3:451\u2013458","journal-title":"ACS Chem Neurosci"},{"key":"3025_CR66","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1021\/cn3000247","volume":"3","author":"S Sinha","year":"2012","unstructured":"Sinha S, Lopes DH, Bitan G (2012) A key role for lysine residues in amyloid beta-protein folding, assembly, and toxicity. ACS Chem Neurosci 3:473\u2013481","journal-title":"ACS Chem Neurosci"},{"key":"3025_CR67","doi-asserted-by":"publisher","first-page":"4433","DOI":"10.1021\/pr0703627","volume":"6","author":"E Portelius","year":"2007","unstructured":"Portelius E, Tran AJ, Andreasson U, Persson R, Brinkmalm G, Zetterberg H, Blennow K, Westman-Brinkmalm A (2007) Characterization of amyloid beta peptides in cerebrospinal fluid by an automated immunoprecipitation procedure followed by mass spectrometry. J Proteome Res 6:4433\u20134439","journal-title":"J Proteome Res"},{"key":"3025_CR68","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1002\/jms.2987","volume":"47","author":"G Brinkmalm","year":"2012","unstructured":"Brinkmalm G, Portelius E, Ohrfelt A, Mattsson N, Persson R, Gustavsson MK, Vite CH, Gobom J, Mansson JE, Nilsson J, Halim A, Larson G, Ruetschi U, Zetterberg H, Blennow K, Brinkmalm A (2012) An online nano-LC-ESI-FTICR-MS method for comprehensive characterization of endogenous fragments from amyloid beta and amyloid precursor protein in human and cat cerebrospinal fluid. J Mass Spectrom 47:591\u2013603","journal-title":"J Mass Spectrom"},{"key":"3025_CR69","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1016\/j.neulet.2019.02.033","volume":"701","author":"E Gkanatsiou","year":"2019","unstructured":"Gkanatsiou E, Portelius E, Toomey CE, Blennow K, Zetterberg H, Lashley T, Brinkmalm G (2019) A distinct brain beta amyloid signature in cerebral amyloid angiopathy compared to Alzheimer\u2019s disease. Neurosci Lett 701:125\u2013131","journal-title":"Neurosci Lett"}],"container-title":["Molecular Neurobiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12035-022-03025-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s12035-022-03025-9\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12035-022-03025-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,9,30]],"date-time":"2022-09-30T08:26:54Z","timestamp":1664526414000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s12035-022-03025-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,9]]},"references-count":69,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2022,11]]}},"alternative-id":["3025"],"URL":"https:\/\/doi.org\/10.1007\/s12035-022-03025-9","relation":{},"ISSN":["0893-7648","1559-1182"],"issn-type":[{"value":"0893-7648","type":"print"},{"value":"1559-1182","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,9]]},"assertion":[{"value":"22 April 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"31 August 2022","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 September 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Non applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics Approval"}},{"value":"Non applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for Publication"}},{"value":"HZ has served at scientific advisory boards for Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics and CogRx, has given lectures in symposia sponsored by Fujirebio, Alzecure and Biogen, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). KB has served as a consultant, at advisory boards, or at data monitoring committees for Abcam, Axon, Biogen, JOMDD\/Shimadzu. Julius Clinical, Lilly, MagQu, Novartis, Prothena, Roche Diagnostics, and Siemens Healthineers, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, all unrelated to the work presented in this paper. MJM is a full-time employee of Servier Pharmaceuticals and has no other interest to declare.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}},{"value":"Non applicable.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Research Involving Human Participants and\/or Animals"}},{"value":"Non applicable.","order":6,"name":"Ethics","group":{"name":"EthicsHeading","label":"Informed Consent"}}]}}