The role of exosomes in the processing of proteins associated with neurodegenerative diseases (original) (raw)
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Perspective Insights of Exosomes in Neurodegenerative Diseases: A Critical Appraisal
Frontiers in aging neuroscience, 2017
Exosomes are small membranous entities of endocytic origin. Their production by a wide variety of cells in eukaryotes implicates their roles in the execution of essential processes, especially cellular communication. Exosomes are secreted under both physiological and pathophysiological conditions, and their actions on neighboring and distant cells lead to the modulations of cellular behaviors. They also assist in the delivery of disease causing entities, such as prions, α-syn, and tau, and thus, facilitate spread to non-effected regions and accelerate the progressions of neurodegenerative diseases. The characterization of exosomes, provides information on aberrant processes, and thus, exosome analysis has many clinical applications. Because they are associated with the transport of different cellular entities across the blood-brain barrier (BBB), exosomes might be useful for delivering drugs and other therapeutic molecules to brain. Herein, we review roles played by exosomes in diff...
Exosomes: vesicular carriers for intercellular communication in neurodegenerative disorders
Cell and Tissue Research, 2012
The intercellular transfer of misfolded proteins has received increasing attention in various neurodegenerative diseases characterized by the aggregation of specific proteins, as observed in Alzheimer's, Parkinson's and Huntington's disease. One hypothesis holds that intercellular dissemination of these aggregates within the central nervous system results in the seeded assembly of the cognate soluble protein in target cells, similar to that proposed for transmissible prion diseases. The molecular mechanisms underlying the intercellular transfer of these proteinaceous aggregates are poorly understood. Various transfer modes of misfolded proteins including continuous cell-cell contacts such as nanotubes, unconventional secretion or microvesicle/exosome-associated dissemination have been suggested. Cells can release proteins, lipids and nucleic acids by vesicular exocytosis pathways destined for horizontal transfer. Encapsulation into microvesicular/exosomal vehicles not only protects these molecules from degradation and dilution in the extracellular space but also facilitates delivery over large distances, e.g. within the blood flow or interstitial fluid. Specific surface ligands might allow the highly efficient and targeted uptake of these vesicles by recipient cells. In this review, we focus on the cell biology and function of neuronal microvesicles/exosomes and discuss the evidence for pathogenic intercellular protein transfer mediated by vesicular carriers.
Alzheimer's disease beta-amyloid peptides are released in association with exosomes
Proceedings of the National Academy of Sciences, 2006
Although the exact etiology of Alzheimer's disease (AD) is a topic of debate, the consensus is that the accumulation of -amyloid (A) peptides in the senile plaques is one of the hallmarks of the progression of the disease. The A peptide is formed by the amyloidogenic cleavage of the amyloid precursor protein (APP) by and ␥-secretases. The endocytic system has been implicated in the cleavages leading to the formation of A. However, the identity of the intracellular compartment where the amyloidogenic secretases cleave and the mechanism by which the intracellularly generated A is released into the extracellular milieu are not clear. Here, we show that -cleavage occurs in early endosomes followed by routing of A to multivesicular bodies (MVBs) in HeLa and N2a cells. Subsequently, a minute fraction of A peptides can be secreted from the cells in association with exosomes, intraluminal vesicles of MVBs that are released into the extracellular space as a result of fusion of MVBs with the plasma membrane. Exosomal proteins were found to accumulate in the plaques of AD patient brains, suggesting a role in the pathogenesis of AD. multivesicular bodies ͉ rafts ͉ amyloid precursor protein ͉ -secretase ͉ endocytosis A lzheimer's disease (AD) is a late-onset neurological disorder with progressive loss of memory and cognitive abilities as a result of excessive neurodegeneration (1). AD is characterized by extracellular aggregates of -amyloid (A) peptides known as amyloid plaques (2). The A peptide is derived from the sequential processing of the amyloid precursor protein (APP) by and ␥-secretases. -secretase [(-APP cleaving enzyme (BACE)] is a type-1 transmembrane aspartyl protease and is mainly localized to endosomes, lysosomes and the trans-Golgi network (3). ␥-Secretase is a multicomponent complex that is composed of presenilin-1͞presenilin-2, nicastrin, Aph-1, and PEN-2 (4) and is localized to the early secretory (5, 6) and the endocytic compartments (7, 8). Nonamyloidogenic processing of APP involves ␣-secretase that cleaves APP inside the A region, giving rise to the ␣-cleaved ectodomain, thus precluding the formation of A (9). Hence, the availability of APP to either ␣or -secretase determines whether A peptide will be generated. Lateral organization of membranes (10) and subcellular localization (11, 12) of the substrate and the secretases have been documented to regulate A generation. Recent work suggests that -secretase associates with lipid rafts, liquid-ordered domains in the membrane , and that integrity of raft domains is required for -cleavage of APP to occur (ref. 10; see, however, ref. 15). ␣-Cleavage, in contrast, occurs outside raft domains (10). The ␥-secretase complex is also raft-associated (16); hence, amyloidogenic processing of APP could occur in clustered raft domains to generate A (10). Inhibition of endocytosis reduces -cleavage but not ␣-cleavage, suggesting that -cleavage mainly occurs in endosomes . Accumulation of A peptides in extracellular plaques requires the release of A peptides from the cell. An intriguing question is how the intracellularly generated, fairly hydrophobic A peptide is released into the extracellular space. Here we show that -cleavage occurs in a specific subset of endosomes and that a fraction of A peptides is found in multivesicular bodies (MVBs) and is released in association with exosomes. Upon fusion of MVBs with the plasma membrane, the intraluminal vesicles of MVBs are released into the extracellular milieu as exosomes. These vesicles are enriched in raft lipids and proteins and are implicated in various functions, such as scavenging of archaic proteins, signaling, and transmission of pathogens (20). In this study, we also show that an exosome-associated protein, Alix, is specifically enriched in amyloid plaques of AD brain sections, suggesting a novel role for exosomes in AD pathogenesis.
Exosomes: Future Perspective in Neurodegenerative Diseases
Negah Institute for Social Research & Scientific Communication , 2020
Neurodegeneration is a progressive and irreversible loss of neuronal cells in specific regions of the brain. Alzheimer Diseases (AD) Parkinson Disease (PD) are the most common forms of neurodegenerative diseases in older people. Exosomes are extracellular nanovesicles that have a key role in physiological processes such as intercellular communication, cell migration, angiogenesis, and anti-tumor immunity. Mounting evidence indicates the role of exosomes in neurodegenerative disorders as possible carriers of disease particles. They have several different potential applications thanks to their unique structure and functions. The present review summarizes recent studies on exosome potentials as a biomarker and therapeutic tool in neurodegenerative diseases. It also provides an overview of the structure and function of exosomes.
Faseb Journal, 2007
Alzheimer's disease (AD) is the most common form of dementia and is associated with the deposition of the 39-to 43-amino acid -amyloid peptide (A) in the brain. C-terminal fragments (CTFs) of amyloid precursor protein (APP) can accumulate in endosomally derived multivesicular bodies (MVBs). These intracellular structures contain intraluminal vesicles that are released from the cell as exosomes when the MVB fuses with the plasma membrane. Here we have investigated the role of exosomes in the processing of APP and show that these vesicles contain APP-CTFs, as well as A. In addition, inhibition of ␥-secretase results in a significant increase in the amount of ␣and -secretase cleavage, further increasing the amount of APP-CTFs contained within these exosomes. We identify several key members of the secretase family of proteases (BACE, PS1, PS2, and ADAM10) to be localized in exosomes, suggesting they may be a previously unidentified site of APP cleavage. These results provide further evidence for a novel pathway in which APP fragments are released from cells and have implications for the analysis of APP processing and diagnostics for Alzheimer's disease.-Sharples, R.
Extracellular Vesicle Biology in Alzheimer’s Disease and Related Tauopathy
Journal of Neuroimmune Pharmacology, 2017
Extracellular vesicles (EVs) are physiological vesicles secreted from most of eukaryotes and contain cargos of their cell of origin. EVs, and particularly a subset of EV known as exosomes, are emerging as key mediators of cell to cell communication and waste management for cells both during normal organismal function and in disease. In this review, we investigate the rapidly growing field of exosome biology, their biogenesis, cargo loading, and uptake by other cells. We particularly consider the role of exosomes in Alzheimer's disease, both as a pathogenic agent and as a disease biomarker. We also explore the emerging role of exosomes in chronic traumatic encephalopathy. Finally, we highlight open questions in these fields and the possible use of exosomes as therapeutic targets and agents.
International Journal of Molecular Sciences
Exosomes (EXOs) were given attention as an extracellular vesicle (EV) with a pivotal pathophysiological role in the development of certain neurodegenerative disorders (NDD), such as Parkinson’s and Alzheimer’s disease (AD). EXOs have shown the potential to carry pathological and therapeutic cargo; thus, researchers have harnessed EXOs in drug delivery applications. EXOs have shown low immunogenicity as natural drug delivery vehicles, thus ensuring efficient drug delivery without causing significant adverse reactions. Recently, EXOs provided potential drug delivery opportunities in AD and promising future clinical applications with the diagnosis of NDD and were studied for their usefulness in disease detection and prediction prior to the emergence of symptoms. In the future, the microfluidics technique will play an essential role in isolating and detecting EXOs to diagnose AD before the development of advanced symptoms. This review is not reiterative literature but will discuss why E...
Exosomes as possible spread factor and potential biomarkers in Alzheimer's disease: current concepts
Biomarkers in Medicine, 2018
Increasing evidence points that important factors during development/spread of Alzheimer's disease in brain tissue are small extracellular vesicles, called exosomes. Exosomes comprise disease-related biomolecules such as the amyloid protein precursor, β-amyloid peptide and tau protein. Exosomes are hypothesized to facilitate the spread of β-amyloid peptide and tau protein from their cells of origin (e.g., neurons) to the extracellular space and to recipient cells to alter their phenotype and function. The roles of exosomes carry a rich biomolecules cargo in physiology and pathology is poorly understood. In this review, we will consider new information about the role of exosomes in Alzheimer's disease spreading and progression and underline their possible usefulness as the future diagnostic antemortem biomarkers in this devastating disorder.
Emerging Role of Genetic Alterations Affecting Exosome Biology in Neurodegenerative Diseases
International Journal of Molecular Sciences
The abnormal deposition of proteins in brain tissue is a common feature of neurodegenerative diseases (NDs) often accompanied by the spread of mutated proteins, causing neuronal toxicity. Exosomes play a fundamental role on their releasing in extracellular space after endosomal pathway activation, allowing to remove protein aggregates by lysosomal degradation or their inclusion into multivesicular bodies (MVBs), besides promoting cellular cross-talk. The emerging evidence of pathogenic mutations associated to ND susceptibility, leading to impairment of exosome production and secretion, opens a new perspective on the mechanisms involved in neurodegeneration. Recent findings suggest to investigate the genetic mechanisms regulating the different exosome functions in central nervous system (CNS), to understand their role in the pathogenesis of NDs, addressing the identification of diagnostic and pharmacological targets. This review aims to summarize the mechanisms underlying exosome bio...