{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T12:09:31Z","timestamp":1753877371614,"version":"3.41.2"},"reference-count":51,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2023,5,17]],"date-time":"2023-05-17T00:00:00Z","timestamp":1684281600000},"content-version":"vor","delay-in-days":16,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"Academia Sinica and the National Science and Technology Council of Taiwan","award":["110-2113-M-001-030","111-2113-M-001-048","111-2113-M-007-015"],"award-info":[{"award-number":["110-2113-M-001-030","111-2113-M-001-048","111-2113-M-007-015"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,5,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Nearly 95% of Alzheimer's disease (AD) occurs sporadically without genetic linkage. Aging, hypertension, high cholesterol content, and diabetes are known nongenomic risk factors of AD. Aggregation of A\u03b2 peptides is an initial event of AD pathogenesis. A\u03b2 peptides are catabolic products of a type I membrane protein called amyloid precursor protein (APP). A\u03b240 is the major product, whereas the 2-residue-longer version, A\u03b242, induces amyloid plaque formation in the AD brain. Since cholesterol content is one risk factor for sporadic AD, we aimed to explore whether cholesterol in the membrane affects the structure of the APP transmembrane region, thereby modulating the \u03b3-secretase cutting behavior. Here, we synthesized several peptides containing the APP transmembrane region (sequence 693\u2013726, corresponding to the A\u03b222\u201355 sequence) with one or two Cys mutations for spin labeling. We performed three electron spin resonance experiments to examine the structural changes of the peptides in liposomes composed of dioleoyl phosphatidylcholine and different cholesterol content. Our results show that cholesterol increases membrane thickness by 10% and peptide length accordingly. We identified that the di-glycine region of A\u03b236\u201340 (sequence VGGVV) exhibits the most profound change in response to cholesterol compared with other segments, explaining how the presence of cholesterol affects the \u03b3-secretase cutting site. This study provides spectroscopic evidence showing how cholesterol modulates the structure of the APP transmembrane region in a lipid bilayer.<\/jats:p>","DOI":"10.1093\/pnasnexus\/pgad162","type":"journal-article","created":{"date-parts":[[2023,5,17]],"date-time":"2023-05-17T07:57:07Z","timestamp":1684310227000},"source":"Crossref","is-referenced-by-count":1,"title":["Cholesterol twists the transmembrane Di-Gly region of amyloid-precursor protein"],"prefix":"10.1093","volume":"2","author":[{"given":"David Tzu-Wei","family":"Wang","sequence":"first","affiliation":[{"name":"Institute of Biological Chemistry, Academia Sinica , Taipei 11529 , Taiwan"},{"name":"Institute of Biochemical Sciences, National Taiwan University , Taipei 10617 , Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tiffany Y C","family":"Tang","sequence":"additional","affiliation":[{"name":"Institute of Biological Chemistry, Academia Sinica , Taipei 11529 , Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chun-Ting","family":"Kuo","sequence":"additional","affiliation":[{"name":"Institute of Biological Chemistry, Academia Sinica , Taipei 11529 , Taiwan"},{"name":"Institute of Biochemical Sciences, National Taiwan University , Taipei 10617 , Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yun-Ting","family":"Yu","sequence":"additional","affiliation":[{"name":"Institute of Biological Chemistry, Academia Sinica , Taipei 11529 , Taiwan"},{"name":"Institute of Biochemical Sciences, National Taiwan University , Taipei 10617 , Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric H L","family":"Chen","sequence":"additional","affiliation":[{"name":"Institute of Biological Chemistry, Academia Sinica , Taipei 11529 , Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9313-6075","authenticated-orcid":false,"given":"Ming-Tao","family":"Lee","sequence":"additional","affiliation":[{"name":"Life Science Group, Scientific Research Division, National Synchrotron Radiation Research Center , Hsinchu 30076 , Taiwan"},{"name":"Department of Physics, National Central University , Zhongli 320317 , Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruei-Fong","family":"Tsai","sequence":"additional","affiliation":[{"name":"Department of Chemistry, National Tsing Hua University , Hsinchu 300044 , Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hung-Ying","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Chemistry, National Tsing Hua University , Hsinchu 300044 , 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