Exosomal cellular prion protein drives fibrillization of amyloid beta and counteracts amyloid beta-mediated neurotoxicity

被引：125

作者：

Falker, Clemens ^{[1
]}

Hartmann, Alexander ^{[1
]}

Guett, Inga ^{[1
]}

Dohler, Frank ^{[1
]}

Altmeppen, Hermann ^{[1
]}

Betzel, Christian ^{[2
,3
]}

Schubert, Robin ^{[2
,3
]}

Thurm, Dana ^{[1
]}

Wegwitz, Florian ^{[4
]}

Joshi, Pooja ^{[5
]}

Verderio, Claudia ^{[5
,6
]}

Krasemann, Susanne ^{[1
]}

Glatzel, Markus ^{[1
]}

机构：

[1] Univ Med Ctr Hamburg Eppendorf, Inst Neuropathol, Hamburg, Germany

[2] Univ Hamburg, Inst Biochem & Mol Biol, Lab Struct Biol Infect & Inflammat, Hamburg, Germany

[3] Hamburg Ctr Ultrafast Imaging, Hamburg, Germany

[4] Univ Med Ctr Gottingen, Dept Translat Canc Res, Gottingen, Germany

[5] IRCCS Humanitas, Rozzano, Italy

[6] CNR, Inst Neurosci, I-20133 Milan, Italy

来源：

JOURNAL OF NEUROCHEMISTRY | 2016年 / 137卷 / 01期

关键词：

Alzheimer's disease; amyloid beta; exosomes; neurodegeneration; neurotoxicity; prion protein knockout; ALZHEIMERS-DISEASE; IN-VIVO; A-BETA; SYNAPTIC-PLASTICITY; CEREBROSPINAL-FLUID; MOUSE MODEL; OLIGOMERS; IMPAIRMENT; ASSEMBLIES; RECEPTOR;

D O I：

10.1111/jnc.13514

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：

Alzheimer's disease is a common neurodegenerative, progressive, and fatal disorder. Generation and deposition of amyloid beta (A) peptides associate with its pathogenesis and small soluble A oligomers show the most pronounced neurotoxic effects and correlate with disease initiation and progression. Recent findings showed that A oligomers bind to the cellular prion protein (PrPC) eliciting neurotoxic effects. The role of exosomes, small extracellular vesicles of endosomal origin, in Alzheimer's disease is only poorly understood. Besides serving as disease biomarkers they may promote A plaque formation, decrease A-mediated synaptotoxicity, and enhance A clearance. Here, we explore how exosomal PrPC connects to protective functions attributed to exosomes in Alzheimer's disease. To achieve this, we generated a mouse neuroblastoma PrPC knockout cell line using transcription activator-like effector nucleases. Using these, as well as SH-SY5Y human neuroblastoma cells, we show that PrPC is highly enriched on exosomes and that exosomes bind amyloid beta via PrPC. Exosomes showed highest binding affinity for dimeric, pentameric, and oligomeric A species. Thioflavin T assays revealed that exosomal PrPC accelerates fibrillization of amyloid beta, thereby reducing neurotoxic effects imparted by oligomeric A. Our study provides further evidence for a protective role of exosomes in A-mediated neurodegeneration and highlights the importance of exosomal PrPC in molecular mechanisms of Alzheimer's disease.

引用

页码：88 / 100

页数：13

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