Cerebrospinal Fluid EV Concentration and Size Are Altered in Alzheimer's Disease and Dementia with Lewy Bodies.

Antonio Longobardi,Roberta Zanardini,Roberta Ghidoni,Roland Nicsanu,Luisa Benussi,Sonia Bellini,Marcella Catania,Pietro Tiraboschi,Clarissa Ferrari,Giuliano Binetti,Giuseppe Di Fede,Rosanna Squitti,Claudia Saraceno

doi:10.3390/cells11030462

Abstract

Alzheimer’s disease (AD), dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD) represent the three major neurodegenerative dementias characterized by abnormal brain protein accumulation. In this study, we investigated extracellular vesicles (EVs) and neurotrophic factors in the cerebrospinal fluid (CSF) of 120 subjects: 36 with AD, 30 with DLB, 34 with FTD and 20 controls. Specifically, CSF EVs were analyzed by Nanoparticle Tracking Analysis and neurotrophic factors were measured with ELISA. We found higher EV concentration and lower EV size in AD and DLB groups compared to the controls. Classification tree analysis demonstrated EV size as the best parameter able to discriminate the patients from the controls (96.7% vs. 3.3%, respectively). The diagnostic performance of the EV concentration/size ratio resulted in a fair discrimination level with an area under the curve of 0.74. Moreover, the EV concentration/size ratio was associated with the p-Tau181/Aβ42 ratio in AD patients. In addition, we described altered levels of cystatin C and progranulin in the DLB and AD groups. We did not find any correlation between neurotrophic factors and EV parameters. In conclusion, the results of this study suggest a common involvement of the endosomal pathway in neurodegenerative dementias, giving important insight into the molecular mechanisms underlying these pathologies.

Highlights

Major neurodegenerative dementias are multifactorial conditions that share key underlying pathophysiological processes
We recently reported that genes controlling key endo-lysosomal processes might be involved in Alzheimer’s disease (AD), FTLD and Dementia with Lewy bodies (DLB) pathogenesis, suggesting an etiological link behind these diseases [39]
We analyzed cerebrospinal fluid (CSF) extracellular vesicles (EVs) in patients affected by AD, DLB and Frontotemporal dementia (FTD), and we found an altered EV profile in the patients’ CSF

Summary

Introduction

Major neurodegenerative dementias are multifactorial conditions that share key underlying pathophysiological processes. Alzheimer’s disease (AD) represents the most common form of dementia in the elderly and is characterized by intra- and extra-cellular amyloid-β (Aβ) peptide aggregates forming the amyloid plaques and by phosphorylated tau protein accumulation in neurofibrillary tangles, pathognomonic of the disease [4,5] These inclusions cause inflammatory and oxidative damage that are crucial for AD onset and progression [6]. Dementia with Lewy bodies (DLB) is one of the most common dementias after AD [7] and shares neuropathological characteristics with AD, such as amyloid plaques [8], but the main feature is the presence of α-synuclein inclusions in neurons, neurites, glia and presynaptic terminals These inclusions cause the formation and the spreading of Lewy bodies widely in various brain areas [9]. Frontotemporal dementia (FTD), another major dementia, is typified by early-onset and by several protein inclusions such as tau, ubiquitin, Fused-in-Sarcoma (FUS) and TAR DNA-binding protein 43 (TDP-43) [10,11]

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Results

Conclusion