Blood-derived amyloid-β protein induces Alzheimer's disease pathologies

被引：161

作者：

Bu, X-L ^{[1
,2
]}

Xiang, Y. ^{[1
,2
]}

Jin, W-S ^{[1
,2
]}

Wang, J. ^{[1
,2
]}

Shen, L-L ^{[1
,2
]}

Huang, Z-L ^{[3
,4
]}

Zhang, K. ^{[5
,6
]}

Liu, Y-H ^{[1
,2
]}

Zeng, F. ^{[1
,2
]}

Liu, J-H ^{[7
,8
]}

Sun, H-L ^{[1
,2
]}

Zhuang, Z-Q ^{[1
,2
]}

Chen, S-H ^{[1
,2
]}

Yao, X-Q ^{[1
,2
]}

Giunta, B. ^{[9
]}

Shan, Y-C ^{[7
]}

Tan, J. ^{[10
]}

Chen, X-W ^{[5
,6
]}

Dong, Z-F ^{[3
,4
]}

Zhou, H-D ^{[1
,2
]}

Zhou, X-F ^{[11
,12
]}

Song, W. ^{[13
]}

Wang, Y-J ^{[1
,2
]}

机构：

[1] Third Mil Med Univ, Daping Hosp, Dept Neurol, 10 Changjiang Branch Rd, Chongqing 400042, Peoples R China

[2] Third Mil Med Univ, Daping Hosp, Ctr Clin Neurosci, Chongqing, Peoples R China

[3] Chongqing Med Univ, Childrens Hosp, Minist Educ, Key Lab Child Dev & Disorders, Chongqing, Peoples R China

[4] Chongqing Med Univ, Childrens Hosp, Chongqing Key Lab Translat Med Res Cognit Dev & L, Chongqing, Peoples R China

[5] Third Mil Med Univ, Brain Res Ctr, Chongqing, Peoples R China

[6] Third Mil Med Univ, State Key Lab Trauma Burns & Combined Injury, Chongqing, Peoples R China

[7] Chinese Acad Sci, Dalian Inst Chem Phys, CAS Key Lab Separat Sci Analyt Chem, Dalian, Peoples R China

[8] Univ Chinese Acad Sci, Beijing, Peoples R China

[9] Univ S Florida, Morsani Coll Med, Dept Psychiat & Behav Neurosci, Neuroimmunol Lab, Tampa, FL USA

[10] Univ S Florida, Morsani Coll Med, Dept Psychiat & Behav Neurosci, Silver Child Dev Ctr,Rashid Lab Dev Neurobiol, Tampa, FL USA

[11] Univ South Australia, Sch Pharm & Med Sci, Adelaide, SA, Australia

[12] Univ South Australia, Sansom Inst, Adelaide, SA, Australia

[13] Univ British Columbia, Dept Psychiat, Townsend Family Labs, Vancouver, BC, Canada

来源：

MOLECULAR PSYCHIATRY | 2018年 / 23卷 / 09期

基金：

中国国家自然科学基金; 加拿大健康研究院;

关键词：

PRECURSOR PROTEIN; SECRETASE ACTIVITY; APOLIPOPROTEIN-E; BRAIN-BARRIER; PEPTIDE; ANGIOPATHY; CLEARANCE; INDUCTION; DENSITY; TISSUES;

D O I：

10.1038/mp.2017.204

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The amyloid-beta protein (A beta) protein plays a pivotal role in the pathogenesis of Alzheimer's disease (AD). It is believed that A beta deposited in the brain originates from the brain tissue itself. However, A beta is generated in both brain and peripheral tissues. Whether circulating A beta contributes to brain AD-type pathologies remains largely unknown. In this study, using a model of parabiosis between APPswe/PS1dE9 transgenic AD mice and their wild-type littermates, we observed that the human A beta originated from transgenic AD model mice entered the circulation and accumulated in the brains of wild-type mice, and formed cerebral amyloid angiopathy and A beta plaques after a 12-month period of parabiosis. AD-type pathologies related to the A beta accumulation including tau hyperphosphorylation, neurodegeneration, neuroinflammation and microhemorrhage were found in the brains of the parabiotic wild-type mice. More importantly, hippocampal CA1 long-term potentiation was markedly impaired in parabiotic wild-type mice. To the best of our knowledge, our study is the first to reveal that blood-derived A beta can enter the brain, form the A beta-related pathologies and induce functional deficits of neurons. Our study provides novel insight into AD pathogenesis and provides evidence that supports the development of therapies for AD by targeting A beta metabolism in both the brain and the periphery.

引用

页码：1948 / 1956

页数：9

共 53 条

[1] Clearance mechanisms of Alzheimer's amyloid-β peptide: implications for therapeutic design and diagnostic tests [J].

Bates, K. A. ;

Verdile, G. ;

Li, Q. -X ;

Ames, D. ;

Hudson, P. ;

Masters, C. L. ;

Martins, R. N. .

MOLECULAR PSYCHIATRY, 2009, 14 (05) :469-486

[2] A SYNAPTIC MODEL OF MEMORY - LONG-TERM POTENTIATION IN THE HIPPOCAMPUS [J].

BLISS, TVP ;

COLLINGRIDGE, GL .

NATURE, 1993, 361 (6407) :31-39

[3] Cerebral amyloid angiopathy and its co-occurrence with Alzheimer's disease and other cerebrovascular neuropathologic changes [J].

Brenowitz, Willa D. ;

Nelson, Peter T. ;

Besser, Lilah M. ;

Heller, Katherine B. ;

Kukull, Walter A. .

NEUROBIOLOGY OF AGING, 2015, 36 (10) :2702-2708

[4] A study on the association between infectious burden and Alzheimer's disease [J].

Bu, X. -L. ;

Yao, X. -Q. ;

Jiao, S. -S. ;

Zeng, F. ;

Liu, Y. -H. ;

Xiang, Y. ;

Liang, C. -R. ;

Wang, Q. -H. ;

Wang, X. ;

Cao, H. -Y. ;

Yi, X. ;

Deng, B. ;

Liu, C. -H. ;

Xu, J. ;

Zhang, L. -L. ;

Gao, C. -Y. ;

Xu, Z. -Q. ;

Zhang, M. ;

Wang, L. ;

Tan, X. -L. ;

Xu, X. ;

Zhou, H. -D. ;

Wang, Y. -J. .

EUROPEAN JOURNAL OF NEUROLOGY, 2015, 22 (12) :1519-1525

[5] Serum Amyloid-Beta Levels are Increased in Patients with Chronic Obstructive Pulmonary Disease [J].

Bu, Xian-Le ;

Cao, Guo-Qiang ;

Shen, Lin-Lin ;

Xiang, Yang ;

Jiao, Shu-Sheng ;

Liu, Yu-Hui ;

Zhu, Chi ;

Zeng, Fan ;

Wang, Qing-Hua ;

Wang, Ye-Ran ;

He, Yong ;

Zhou, Hua-Dong ;

Wang, Yan-Jiang .

NEUROTOXICITY RESEARCH, 2015, 28 (04) :346-351

[6] PLATELETS ARE THE PRIMARY SOURCE OF AMYLOID BETA-PEPTIDE IN HUMAN BLOOD [J].

CHEN, M ;

INESTROSA, NC ;

ROSS, GS ;

FERNANDEZ, HL .

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1995, 213 (01) :96-103

[7] EXCESSIVE PRODUCTION OF AMYLOID BETA-PROTEIN BY PERIPHERAL CELLS OF SYMPTOMATIC AND PRESYMPTOMATIC PATIENTS CARRYING THE SWEDISH FAMILIAL ALZHEIMER-DISEASE MUTATION [J].

CITRON, M ;

VIGOPELFREY, C ;

TEPLOW, DB ;

MILLER, C ;

SCHENK, D ;

JOHNSTON, J ;

WINBLAD, B ;

VENIZELOS, N ;

LANNFELT, L ;

SELKOE, DJ .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1994, 91 (25) :11993-11997

[8] RAGE mediates amyloid-β peptide transport across the blood-brain barrier and accumulation in brain [J].

Deane, R ;

Yan, SD ;

Submamaryan, RK ;

LaRue, B ;

Jovanovic, S ;

Hogg, E ;

Welch, D ;

Manness, L ;

Lin, C ;

Yu, J ;

Zhu, H ;

Ghiso, J ;

Frangione, B ;

Stern, A ;

Schmidt, AM ;

Armstrong, DL ;

Arnold, B ;

Liliensiek, B ;

Nawroth, P ;

Hofman, F ;

Kindy, M ;

Stern, D ;

Zlokovic, B .

NATURE MEDICINE, 2003, 9 (07) :907-913

[9] Role of the blood-brain barrier in the pathogenesis of Alzheimer's disease [J].

Deane, Rashid ;

Zlokovic, Berislav V. .

CURRENT ALZHEIMER RESEARCH, 2007, 4 (02) :191-197

[10] ABCG2- and ABCG4-Mediated Efflux of Amyloid-β Peptide (1-40) at the Mouse Blood-Brain Barrier [J].

Do, Tuan Minh ;

Noel-Hudson, Marie-Sophie ;

Ribes, Sandy ;

Besengez, Capucine ;

Smirnova, Maria ;

Cisternino, Salvatore ;

Buyse, Marion ;

Calon, Frederic ;

Chimini, Giovanna ;

Chacun, Helene ;

Scherrmann, Jean-Michel ;

Farinotti, Robert ;

Bourasset, Fanchon .

JOURNAL OF ALZHEIMERS DISEASE, 2012, 30 (01) :155-166

← 1 2 3 4 5 6 →