High glucose promotes Aβ production by inhibiting APP degradation.

Abnormal deposition of neuriticplaques is the uniqueneuropathological hallmark of Alzheimer's disease (AD).Amyloid β protein (Aβ), the major component of plaques, is generated from sequential cleavage of amyloidβ precursor protein (APP) by β-secretase and γ-secretase complex. Patients with diab...

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Main Authors: Yi Yang, Yili Wu, Shuting Zhang, Weihong Song
Format: Article
Language:English
Published: Public Library of Science (PLoS) 2013-01-01
Series:PLoS ONE
Online Access:http://europepmc.org/articles/PMC3720941?pdf=render
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spelling doaj-40451836922645d49116f7bb29906ad22020-11-25T01:44:58ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-0187e6982410.1371/journal.pone.0069824High glucose promotes Aβ production by inhibiting APP degradation.Yi YangYili WuShuting ZhangWeihong SongAbnormal deposition of neuriticplaques is the uniqueneuropathological hallmark of Alzheimer's disease (AD).Amyloid β protein (Aβ), the major component of plaques, is generated from sequential cleavage of amyloidβ precursor protein (APP) by β-secretase and γ-secretase complex. Patients with diabetes mellitus (DM), characterized by chronic hyperglycemia,have increased risk of AD development.However, the role of high blood glucose in APP processing and Aβ generation remains elusive. In this study, we investigated the effect of high glucose on APP metabolism and Aβ generation in cultured human cells. We found that high glucose treatment significantly increased APP protein level in both neuronal-like and non-neuronal cells, and promoted Aβ generation. Furthermore, we found that high glucose-induced increase of APP level was not due to enhancement of APP gene transcription but resulted from inhibition of APP protein degradation. Taken together, our data indicated that hyperglycemia could promote AD pathogenesis by inhibiting APP degradation and enhancing Aβ production. More importantly, the elevation of APP level and Aβ generation by high glucose was caused by reduction of APP turnover rate.Thus,our study provides a molecular mechanism of increased risk of developing AD in patients withDMand suggests thatglycemic control might be potentially beneficial for reducing the incidence of AD in diabetic patients and delaying the AD progression.http://europepmc.org/articles/PMC3720941?pdf=render
collection DOAJ
language English
format Article
sources DOAJ
author Yi Yang
Yili Wu
Shuting Zhang
Weihong Song
spellingShingle Yi Yang
Yili Wu
Shuting Zhang
Weihong Song
High glucose promotes Aβ production by inhibiting APP degradation.
PLoS ONE
author_facet Yi Yang
Yili Wu
Shuting Zhang
Weihong Song
author_sort Yi Yang
title High glucose promotes Aβ production by inhibiting APP degradation.
title_short High glucose promotes Aβ production by inhibiting APP degradation.
title_full High glucose promotes Aβ production by inhibiting APP degradation.
title_fullStr High glucose promotes Aβ production by inhibiting APP degradation.
title_full_unstemmed High glucose promotes Aβ production by inhibiting APP degradation.
title_sort high glucose promotes aβ production by inhibiting app degradation.
publisher Public Library of Science (PLoS)
series PLoS ONE
issn 1932-6203
publishDate 2013-01-01
description Abnormal deposition of neuriticplaques is the uniqueneuropathological hallmark of Alzheimer's disease (AD).Amyloid β protein (Aβ), the major component of plaques, is generated from sequential cleavage of amyloidβ precursor protein (APP) by β-secretase and γ-secretase complex. Patients with diabetes mellitus (DM), characterized by chronic hyperglycemia,have increased risk of AD development.However, the role of high blood glucose in APP processing and Aβ generation remains elusive. In this study, we investigated the effect of high glucose on APP metabolism and Aβ generation in cultured human cells. We found that high glucose treatment significantly increased APP protein level in both neuronal-like and non-neuronal cells, and promoted Aβ generation. Furthermore, we found that high glucose-induced increase of APP level was not due to enhancement of APP gene transcription but resulted from inhibition of APP protein degradation. Taken together, our data indicated that hyperglycemia could promote AD pathogenesis by inhibiting APP degradation and enhancing Aβ production. More importantly, the elevation of APP level and Aβ generation by high glucose was caused by reduction of APP turnover rate.Thus,our study provides a molecular mechanism of increased risk of developing AD in patients withDMand suggests thatglycemic control might be potentially beneficial for reducing the incidence of AD in diabetic patients and delaying the AD progression.
url http://europepmc.org/articles/PMC3720941?pdf=render
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AT yiliwu highglucosepromotesabproductionbyinhibitingappdegradation
AT shutingzhang highglucosepromotesabproductionbyinhibitingappdegradation
AT weihongsong highglucosepromotesabproductionbyinhibitingappdegradation
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