A pleiotropic role for exosomes loaded with the amyloid β precursor protein carboxyl-terminal fragments in the brain of Down syndrome patients

NEUROBIOLOGY OF AGING

卷:84

Article

Perez-Gonzalez, Rocio^1,2  Gauthier, Sebastien A.¹  Sharma, Ajay¹  Miller, Chelsea¹  Pawlik, Monika¹  Kaur, Gurjinder¹  Kim, Yohan^1,2  Levy, Efrat^1,2,3,4 

[1] Nathan S Kline Inst Psychiat Res, Ctr Dementia Res, Orangeburg, NY 10962 USA

[2] NYU Langone Hlth, Dept Psychiat, New York, NY USA

[3] NYU Langone Hlth, Dept Biochem & Mol Pharmacol, New York, NY USA

[4] NYU Langone Hlth, Neurosci Inst, New York, NY USA

关键词: Extracellular vesicles;    Exosomes;    Brain;    Down syndrome;    APP;    APP-CTFs;    Aging;   

DOI  :  10.1016/j.neurobiolaging.2019.07.016

来源: Elsevier

【 摘 要 】

Down syndrome (DS) is characterized by cognitive deficits throughout the life span and with the development of aging-dependent Alzheimer's type neuropathology, which is related to the triplication of the amyloid beta precursor protein (APP) gene. A dysfunctional endosomal system in neurons is an early characteristic of DS and APP metabolites accumulate in endosomes in DS neurons. We have previously shown enhanced release of exosomes in the brain of DS patients and the mouse model of DS Ts [Rb(12.17(16))12Cje (Ts2), and by DS fibroblasts, as compared with diploid controls. Here, we demonstrate that exosome-enriched extracellular vesicles (hereafter called EVs) isolated from DS and Ts2 brains, and from the culture media of human DS fibroblasts are enriched in APP carboxyl-terminal fragments (APP-CIFs) as compared with diploid controls. Moreover, APP-CTFs levels increase in an age-dependent manner in EVs isolated from the brain of Ts2 mice. The release of APP-CTFs-enriched exosomes may have a pathogenic role by transporting APP-CTFs into naive neurons and propagating these neurotoxic metabolites, which are also a source of amyloid beta, throughout the brain, but also provides a benefit to DS neurons by shedding APP-CTFs accumulated intracellularly. (C) 2019 Elsevier Inc. All rights reserved.

【 授权许可】

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