Synthesis of human amyloid restricted to liver results in an Alzheimer disease-like neurodegenerative phenotype

被引：53

作者：

Lam, Virginie ^{[1
,2
]}

Takechi, Ryusuke ^{[1
,2
]}

Hackett, Mark J. ^{[1
,3
]}

Francis, Roslyn ^{[4
,5
]}

Bynevelt, Michael ^{[6
]}

Celliers, Liesl M. ^{[4
,7
]}

Nesbit, Michael ^{[1
,2
]}

Mamsa, Somayra ^{[1
]}

Arfuso, Frank ^{[1
]}

Das, Sukanya ^{[1
]}

Koentgen, Frank ^{[8
]}

Hagan, Maree ^{[8
]}

Codd, Lincoln ^{[9
]}

Richardson, Kirsty ^{[10
]}

O'Mara, Brenton ^{[4
]}

Scharli, Rainer K. ^{[11
,12
]}

Morandeau, Laurence ^{[11
,12
]}

Gauntlett, Jonathan ^{[8
]}

Leatherday, Christopher ^{[13
]}

Boucek, Jan ^{[13
]}

Mamo, John C. L. ^{[1
,2
]}

机构：

[1] Curtin Univ, Fac Hlth Sci, Curtin Hlth Innovat Res Inst, Bentley, WA, Australia

[2] Curtin Univ, Fac Hlth Sci, Sch Populat Hlth, Bentley, WA, Australia

[3] Curtin Univ, Fac Sci & Engn, Sch Mol & Life Sci, Bentley, WA, Australia

[4] Sir Charles Gairdner Hosp, Dept Nucl Med, Nedlands, WA, Australia

[5] Univ Western Australia, Sch Med & Pharmacol, Crawley, Australia

[6] Sir Charles Gairdner Hosp, Nedlands, WA, Australia

[7] Fiona Stanley Hosp, Dept Mol Imaging & Therapy Serv, Murdoch, WA, Australia

[8] Ozgene Pty Ltd, Bentley, WA, Australia

[9] Sir Charles Gairdner Hosp, Dept Radiol, Nedlands, WA, Australia

[10] Univ Western Australia, Ctr Med Res, QEII Med Ctr, Harry Perkins Inst Med Res,Lab Canc Med, Nedlands, WA, Australia

[11] Sir Charles Gairdner Hosp, Radiopharmaceut Prod & Dev Ctr RAPID, PET Labs, Nedlands, WA, Australia

[12] Univ Western Australia, Phys, Nedlands, WA, Australia

[13] East Metropolitan Hlth Serv, Hlth Technol Management Unit, Perth, WA, Australia

来源：

PLOS BIOLOGY | 2021年 / 19卷 / 09期

基金：

英国医学研究理事会;

关键词：

BLOOD-BRAIN-BARRIER; A-BETA; TRANSGENIC MICE; APOLIPOPROTEIN-B; MOUSE MODELS; PLASMA; PLAQUES; GENE; HOMEOSTASIS; COLOCALIZATION;

D O I：

10.1371/journal.pbio.3001358

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：

Several lines of study suggest that peripheral metabolism of amyloid beta (Ass) is associated with risk for Alzheimer disease (AD). In blood, greater than 90% of Ass is complexed as an apolipoprotein, raising the possibility of a lipoprotein-mediated axis for AD risk. In this study, we report that genetic modification of C57BL/6J mice engineered to synthesise human Ass only in liver (hepatocyte-specific human amyloid (HSHA) strain) has marked neurodegeneration concomitant with capillary dysfunction, parenchymal extravasation of lipoprotein-Ass, and neurovascular inflammation. Moreover, the HSHA mice showed impaired performance in the passive avoidance test, suggesting impairment in hippocampal-dependent learning. Transmission electron microscopy shows marked neurovascular disruption in HSHA mice. This study provides causal evidence of a lipoprotein-Ass /capillary axis for onset and progression of a neurodegenerative process.

引用

页数：26

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