Changes in the Morphology, Number, and Protein Levels of Plasma Exosomes in CADASIL Patients

Article type: Research Article

Authors: Gao, Dandan^{a; 1} | Shang, Junkui^{a; 1} | Sun, Ruihua^b | Shi, Yingying^c | Jiang, Haisong^d | Ma, Mingming^{a; *} | Zhang, Jiewen^{a; *}

Affiliations: [a] Department of Neurology, Zhengzhou University People’s Hospital, Henan Provincial People’s Hospital, Zhengzhou, Henan, China | [b] Department of Neurology, Henan University People’s Hospital, Zhengzhou, Henan, China | [c] Department of Neurology, Henan Provincial People’s Hospital, Zhengzhou, Henan, China | [d] Institute of Neurology, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Chengdu, China

Correspondence: [*] Correspondence to: Mingming Ma, Department of Neurology, Zhengzhou University People’s Hospital, Henan Provincial People’s Hospital, Zhengzhou, 450003, Henan, China. Tel.: +86 0371 65807586; E-mail: macklon12@163.com and Jiewen Zhang, Department of Neurology, Zhengzhou University People’s Hospital, Henan Provincial People’s Hospital, Zhengzhou, 450003, Henan, China. Tel.: +86 0371 65580171; E-mail: zhangjiewen9900@126.com.

Note: [1] These authors contributed equally to this work.

Abstract: Background:Exosomes are nano-sized extracellular vesicles which are secreted by cells and usually found in body fluids. Previous research has shown that exosomal secretion and autophagy-lysosomal pathway synergistically participates in intracellular abnormal protein elimination. The main pathological manifestations of Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is abnormal accumulation of mutant NOTCH3, and CADASIL vascular smooth muscle cells have been found with autophagy-lysosomal dysfunction. However, whether plasma exosomes change in CADASIL patients is still unclear. Objective:We are aimed to investigate the differences of plasma exosomes between CADASIL patients and healthy controls. Methods:The subjects included 30 CADASIL patients and 30 healthy controls without NOTCH3 mutation. The severity of white matter lesions (WMLs) of CADASIL patients was quantified by Fazekas score. Transmission electron microscopy and nanoparticle tracking analysis were performed to characterize plasma exosomes. In addition, NOTCH3, Neurofilament light and Aβ42 levels in plasma exosomes were quantified by enzyme-linked immunosorbent assays. Results:We found that exosomes from CADASIL patients were lower in quantity. In addition, CADASIL plasma exosomes had significantly lower levels of NOTCH3 and significantly increased levels of NFL than those of matched healthy subjects. Interestingly, plasma exosome NOTCH3 levels of CADASIL patients significantly correlated with severity of WMLs. Conclusion:The exosome NOTCH3 may be related to the pathological changes of CADASIL, which provides a basis for the pathogenesis research of CADASIL. In addition, plasma exosome NOTCH3 and NFL levels may act as biomarkers to monitor and predict disease progression and measure therapeutic effectiveness in the future clinical trials.

Keywords: CADASIL, exosomes, nanoparticle tracking analysis, neurofilament light, NOTCH3, transmission electron microscopy

DOI: 10.3233/JAD-210101

Journal: Journal of Alzheimer's Disease, vol. 81, no. 1, pp. 221-229, 2021