CNS-Derived Blood Exosomes as a Promising Source of Biomarkers: Opportunities and Challenges

Hornung, Simon; Dutta, Suman; Bitan, Gal

doi:10.3389/fnmol.2020.00038

Cited by 156 publications

(162 citation statements)

References 137 publications

(211 reference statements)

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“…Analysis of biomarkers in CNS-derived exosomes isolated from the blood is a new approach that offers a minimally invasive, unique window into biochemical changes in the brain (49,50). This methodology has been applied to the measurement of tau in neuronal exosomes from patients with AD, FTD, and other diseases (51-54).…”

Section: Assessment Of Total Tau In Cns-derived Exosomes As a Biomarkmentioning

confidence: 99%

The molecular tweezer CLR01 improves behavioral deficits and reduces tau pathology in P301S-tau transgenic mice

Siddique

et al. 2020

Preprint

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Background: Molecular tweezers (MTs) are broad-spectrum inhibitors of abnormal protein aggregation. A lead MT, called CLR01, has been demonstrated to inhibit the aggregation and toxicity of multiple amyloidogenic proteins in vitro and in vivo. Previously, we evaluated the effect of CLR01 in the 3×Tg mouse model of Alzheimer’s disease, which overexpresses mutant human presenilin 1, amyloid β-protein precursor, and tau and found that subcutaneous administration of the compound for one month led to a robust reduction of amyloid plaques, neurofibrillary tangles, and microgliosis. CLR01 also has been demonstrated to inhibit tau aggregation in vitro and tau seeding in cell culture, yet because in Alzheimer’s disease (AD) and in the 3×Tg model, tau hyperphosphorylation and aggregation are thought to be downstream of Aβ insults, the study in this model left the question whether CLR01 affected tau in vivo directly or indirectly open.Methods: To determine if CLR01 could ameliorate tau pathology directly in vivo, we tested the compound similarly using the P301S-tau (line PS19) mouse model. Mice were administered 0.3- or 1.0-mg/Kg per day CLR01 and tested for muscle strength and behavioral deficits, including anxiety- and disinhibition-like behavior. Their brains then were analyzed by immunohistochemical and biochemical assays for pathological forms of tau, neurodegeneration, and glial pathology.Results: CLR01 treatment ameliorated muscle-strength deterioration, anxiety-, and disinhibition-like behavior. Improved phenotype was associated with decreased levels of pathologic tau forms, suggesting that CLR01 exerts a direct effect on tau in vivo. Limitations of the study included a relatively short treatment period of the mice at an age in which full pathology is not yet developed. In addition, high variability in this model lowered the statistical significance of the findings of some outcome measures.Conclusions: The findings suggest that CLR01 is a particularly attractive candidate for the treatment of AD because it targets simultaneously the two major pathogenic proteins instigating and propagating the disease, amyloid β-protein (Aβ) and tau, respectively. In addition, our study suggests that CLR01 can be used for the treatment of other tauopathies in the absence of amyloid pathology.

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Section: Assessment Of Total Tau In Cns-derived Exosomes As a Biomarkmentioning

confidence: 99%

The molecular tweezer CLR01 improves behavioral deficits and reduces tau pathology in P301S-tau transgenic mice

Siddique

et al. 2020

Preprint

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“…Thus, exosomes derived from body fluids, and the miRNAs contained in them, were studied for biomarker profiling [ 87 ]. Exosomal miRNAs from CNS can provide information from their originating cells in order to accurately follow the state of the nervous system cells and brain tissues [ 96 ]. …”

Section: Discussionmentioning

confidence: 99%

“…Exosomal miRNAs from CNS can provide information from their originating cells in order to accurately follow the state of the nervous system cells and brain tissues [ 96 ].…”

Section: Discussionmentioning

confidence: 99%

Exosomal miRNAs as Potential Diagnostic Biomarkers in Alzheimer’s Disease

et al. 2020

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Alzheimer’s disease (AD), a neurodegenerative disease, is linked to a variety of internal and external factors present from the early stages of the disease. There are several risk factors related to the pathogenesis of AD, among these exosomes and microRNAs (miRNAs) are of particular importance. Exosomes are nanocarriers released from many different cell types, including neuronal cells. Through the transfer of bioactive molecules, they play an important role both in the maintenance of physiological and in pathological conditions. Exosomes could be carriers of potential biomarkers useful for the assessment of disease progression and for therapeutic applications. miRNAs are small noncoding endogenous RNA sequences active in the regulation of protein expression, and alteration of miRNA expression can result in a dysregulation of key genes and pathways that contribute to disease development. Indeed, the involvement of exosomal miRNAs has been highlighted in various neurodegenerative diseases, and this opens the possibility that dysregulated exosomal miRNA profiles may influence AD disease. The advances in exosome-related biomarker detection in AD are summarized. Finally, in this review, we highlight the use of exosomal miRNAs as essential biomarkers in preclinical and clinical studies in Alzheimer’s disease, also taking a look at their potential clinical value.

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“…While much of the work has been on exosomes derived from cells that comprise peripheral tissues, they clearly play an important role in brain function as well. However, while their role as potential biomarkers of disease has received a good deal of attention [ 38 , 49 , 50 ], an understanding of their role in normal brain physiology has lagged behind. I hope that this short review describing their early discovery and characterization as adherons will promote more interest in this important and understudied area of research.…”

Section: Discussionmentioning

confidence: 99%

A Brief History of Adherons: The Discovery of Brain Exosomes

Schubert

2020

IJMS

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Although exosomes were first described in reticulocytes in 1983, many people do not realize that similar vesicles had been studied in the context of muscle and nerve, beginning in 1980. At the time of their discovery, these vesicles were named adherons, and they were found to play an important role in both cell–substrate and cell–cell adhesion. My laboratory described several molecules that are present in adherons, including heparan sulfate proteoglycans (HSPGs) and purpurin. HSPGs have since been shown to play a variety of key roles in brain physiology. Purpurin has a number of important functions in the retina, including a role in nerve cell differentiation and regeneration. In this review, I discuss the discovery of adherons and how that led to continuing studies on their role in the brain with a particular focus on HSPGs.

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CNS-Derived Blood Exosomes as a Promising Source of Biomarkers: Opportunities and Challenges

Cited by 156 publications

References 137 publications

The molecular tweezer CLR01 improves behavioral deficits and reduces tau pathology in P301S-tau transgenic mice

The molecular tweezer CLR01 improves behavioral deficits and reduces tau pathology in P301S-tau transgenic mice

Exosomal miRNAs as Potential Diagnostic Biomarkers in Alzheimer’s Disease

A Brief History of Adherons: The Discovery of Brain Exosomes

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