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Cholesterol twists the transmembrane Di-Gly region of amyloid-precursor protein

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 Aβ peptides is an initial event of AD pathogenesis. Aβ peptides are catabolic products of a typ...

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Autores principales: Wang, David Tzu-Wei, Tang, Tiffany Y C, Kuo, Chun-Ting, Yu, Yun-Ting, Chen, Eric H L, Lee, Ming-Tao, Tsai, Ruei-Fong, Chen, Hung-Ying, Chiang, Yun-Wei, Chen, Rita P Y
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2023
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10230161/
https://www.ncbi.nlm.nih.gov/pubmed/37265546
http://dx.doi.org/10.1093/pnasnexus/pgad162
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author Wang, David Tzu-Wei
Tang, Tiffany Y C
Kuo, Chun-Ting
Yu, Yun-Ting
Chen, Eric H L
Lee, Ming-Tao
Tsai, Ruei-Fong
Chen, Hung-Ying
Chiang, Yun-Wei
Chen, Rita P Y
author_facet Wang, David Tzu-Wei
Tang, Tiffany Y C
Kuo, Chun-Ting
Yu, Yun-Ting
Chen, Eric H L
Lee, Ming-Tao
Tsai, Ruei-Fong
Chen, Hung-Ying
Chiang, Yun-Wei
Chen, Rita P Y
author_sort Wang, David Tzu-Wei
collection PubMed
description 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 Aβ peptides is an initial event of AD pathogenesis. Aβ peptides are catabolic products of a type I membrane protein called amyloid precursor protein (APP). Aβ40 is the major product, whereas the 2-residue-longer version, Aβ42, 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 γ-secretase cutting behavior. Here, we synthesized several peptides containing the APP transmembrane region (sequence 693–726, corresponding to the Aβ(22–55) 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 Aβ(36–40) (sequence VGGVV) exhibits the most profound change in response to cholesterol compared with other segments, explaining how the presence of cholesterol affects the γ-secretase cutting site. This study provides spectroscopic evidence showing how cholesterol modulates the structure of the APP transmembrane region in a lipid bilayer.
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spelling pubmed-102301612023-06-01 Cholesterol twists the transmembrane Di-Gly region of amyloid-precursor protein Wang, David Tzu-Wei Tang, Tiffany Y C Kuo, Chun-Ting Yu, Yun-Ting Chen, Eric H L Lee, Ming-Tao Tsai, Ruei-Fong Chen, Hung-Ying Chiang, Yun-Wei Chen, Rita P Y PNAS Nexus Biological, Health, and Medical Sciences 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 Aβ peptides is an initial event of AD pathogenesis. Aβ peptides are catabolic products of a type I membrane protein called amyloid precursor protein (APP). Aβ40 is the major product, whereas the 2-residue-longer version, Aβ42, 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 γ-secretase cutting behavior. Here, we synthesized several peptides containing the APP transmembrane region (sequence 693–726, corresponding to the Aβ(22–55) 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 Aβ(36–40) (sequence VGGVV) exhibits the most profound change in response to cholesterol compared with other segments, explaining how the presence of cholesterol affects the γ-secretase cutting site. This study provides spectroscopic evidence showing how cholesterol modulates the structure of the APP transmembrane region in a lipid bilayer. Oxford University Press 2023-05-17 /pmc/articles/PMC10230161/ /pubmed/37265546 http://dx.doi.org/10.1093/pnasnexus/pgad162 Text en © The Author(s) 2023. Published by Oxford University Press on behalf of National Academy of Sciences. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Biological, Health, and Medical Sciences
Wang, David Tzu-Wei
Tang, Tiffany Y C
Kuo, Chun-Ting
Yu, Yun-Ting
Chen, Eric H L
Lee, Ming-Tao
Tsai, Ruei-Fong
Chen, Hung-Ying
Chiang, Yun-Wei
Chen, Rita P Y
Cholesterol twists the transmembrane Di-Gly region of amyloid-precursor protein
title Cholesterol twists the transmembrane Di-Gly region of amyloid-precursor protein
title_full Cholesterol twists the transmembrane Di-Gly region of amyloid-precursor protein
title_fullStr Cholesterol twists the transmembrane Di-Gly region of amyloid-precursor protein
title_full_unstemmed Cholesterol twists the transmembrane Di-Gly region of amyloid-precursor protein
title_short Cholesterol twists the transmembrane Di-Gly region of amyloid-precursor protein
title_sort cholesterol twists the transmembrane di-gly region of amyloid-precursor protein
topic Biological, Health, and Medical Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10230161/
https://www.ncbi.nlm.nih.gov/pubmed/37265546
http://dx.doi.org/10.1093/pnasnexus/pgad162
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