Abstract
Alzheimer’s disease (AD), frontotemporal dementia (FTD), and dementia with Lewy bodies (DLB) are the three major neurodegenerative dementias. In this study, we provide evidence that an alteration in extracellular vesicles (EVs) release is common across the three most common neurodegenerative dementias, AD, DLB, and FTD. Specifically, we analyzed plasma EVs in three groups of patients affected by AD, DLB, and FTD, and we found a significant reduction in EVs concentration and larger EVs size in all patient groups. We then investigated whether the loss of neurotrophic factors is also a common pathogenic mechanism among FTD, DLB, and AD, and if levels of neurotrophic factors might affect EVs release. Plasma levels of progranulin and cystatin C (CysC) were partially altered; however, taking together all variables significantly associated with the diagnostic groups only EVs size and concentration were able to distinguish patients from controls. The diagnostic performance of these two EVs parameters together (ratio) was high, with a sensitivity of 83.3% and a specificity of 86.7%, able to distinguish patients from controls but not to differentiate the different forms of dementias. Among the candidate neurotrophic factors, only CysC levels were associated with EVs concentration. Our study suggests that an alteration in the intercellular communication mediated by EVs might be a common molecular pathway underlying neurodegenerative dementias. The identification of shared disease mechanisms is of pivotal importance to develop treatments to delay disease progression. To this aim, further studies investigating plasma EVs size and concentration as early biomarkers of dementia are required.
Highlights
Alzheimer’s disease (AD), frontotemporal dementia (FTD), and dementia with Lewy bodies (DLB) are the three major neurodegenerative dementias
nanoparticle tracking analysis (NTA) showed a significant decrease in plasma extracellular vesicles (EVs) concentration in AD, DLB, and FTD samples compared to CTRL samples (Table 1 and Figures 1A,B) (p < 0.001, one-way ANOVA test with Bonferroni’s post test, CTRL vs. AD, DLB, FIGURE 1 | EVs concentration and size in patient and control groups. (A) Representative spectra from NTA of CTRL, AD, DLB, and FTD plasma EVs. (B) Quantification of EVs concentration with NTA in CTRL, AD, DLB, and FTD plasma samples
We provide evidence that an alteration in EVs release is common across the three most common neurodegenerative dementias, AD, DLB, and FTD and that plasma EVs dosage and size characterization might be a promising marker for dementias
Summary
Alzheimer’s disease (AD), frontotemporal dementia (FTD), and dementia with Lewy bodies (DLB) are the three major neurodegenerative dementias. FTD-causing progranulin null mutations cause a loss of progranulin (PGRN), a neurotrophic factor (Ghidoni et al, 2008b); we demonstrated that PGRN, a protein targeted to the classical secretory pathway, is secreted in association with exosomes by human primary fibroblasts and that null mutations in the GRN gene strongly reduce the number of released exosomes and alter their composition (Benussi et al, 2016). Brain-derived neurotrophic factor (BDNF), a key regulator of neuronal survival, was suggested to play an important role in the pathophysiology of neurodegenerative diseases including AD, FTD, and DLB (Ventriglia et al, 2013; Mitre et al, 2017). A systemic administration of glial-derived neurotrophic factor (GDNF)-expressing macrophages significantly ameliorated neurodegeneration and neuroinflammation in PD mice, and one of the suggested mechanisms for this effect was the release of exosomes containing the GDNF, followed by the efficient GDNF transfer to target neurons (Zhao et al, 2014)
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