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

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