Exosome Production Is Key to Neuronal Endosomal Pathway Integrity in Neurodegenerative Diseases (original) (raw)
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Acta neuropathologica communications, 2017
A dysfunctional endosomal pathway and abnormally enlarged early endosomes in neurons are an early characteristic of Down syndrome (DS) and Alzheimer's disease (AD). We have hypothesized that endosomal material can be released by endosomal multivesicular bodies (MVBs) into the extracellular space via exosomes to relieve neurons of accumulated endosomal contents when endosomal pathway function is compromised. Supporting this, we found that exosome secretion is enhanced in the brains of DS patients and a mouse model of the disease, and by DS fibroblasts. Furthermore, increased levels of the tetraspanin CD63, a regulator of exosome biogenesis, were observed in DS brains. Importantly, CD63 knockdown diminished exosome release and worsened endosomal pathology in DS fibroblasts. Taken together, these data suggest that increased CD63 expression enhances exosome release as an endogenous mechanism mitigating endosomal abnormalities in DS. Thus, the upregulation of exosome release represen...
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...
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...
Apolipoprotein E4 genotype compromises brain exosome production
Brain, 2018
In addition to being the greatest genetic risk factor for Alzheimer's disease, expression of the "4 allele of apolipoprotein E can lead to cognitive decline during ageing that is independent of Alzheimer's amyloid-b and tau pathology. In human post-mortem tissue and mouse models humanized for apolipoprotein E, we examined the impact of apolipoprotein E4 expression on brain exosomes, vesicles that are produced within and secreted from late-endocytic multivesicular bodies. Compared to humans or mice homozygous for the risk-neutral "3 allele we show that the "4 allele, whether homozygous or heterozygous with an "3 allele, drives lower exosome levels in the brain extracellular space. In mice, we show that the apolipoprotein E4-driven change in brain exosome levels is age-dependent: while not present at age 6 months, it is detectable at 12 months of age. Expression levels of the exosome pathway regulators tumor susceptibility gene 101 (TSG101) and Ras-related protein Rab35 (RAB35) were found to be reduced in the brain at the protein and mRNA levels, arguing that apolipoprotein E4 genotype leads to a downregulation of exosome biosynthesis and release. Compromised exosome production is likely to have adverse effects, including diminishing a cell's ability to eliminate materials from the endosomal-lysosomal system. This reduction in brain exosome levels in 12-month-old apolipoprotein E4 mice occurs earlier than our previously reported brain endosomal pathway changes, arguing that an apolipoprotein E4-driven failure in exosome production plays a primary role in endosomal and lysosomal deficits that occur in apolipoprotein E4 mouse and human brains. Disruption of these interdependent endosomal-exosomal-lysosomal systems in apolipoprotein E4-expressing individuals may contribute to amyloidogenic amyloid-b precursor protein processing, compromise trophic signalling and synaptic function, and interfere with a neuron's ability to degrade material, all of which are events that lead to neuronal vulnerability and higher risk of Alzheimer's disease development. Together, these data suggest that exosome pathway dysfunction is a previously unappreciated component of the brain pathologies that occur as a result of apolipoprotein E4 expression.
Altered lysosomal proteins in neural-derived plasma exosomes in preclinical Alzheimer disease
Neurology, 2015
Diverse autolysosomal proteins were quantified in neurally derived blood exosomes from patients with Alzheimer disease (AD) and controls to investigate disordered neuronal autophagy. Blood exosomes obtained once from patients with AD (n = 26) or frontotemporal dementia (n = 16), other patients with AD (n = 20) both when cognitively normal and 1 to 10 years later when diagnosed, and case controls were enriched for neural sources by anti-human L1CAM antibody immunoabsorption. Extracted exosomal proteins were quantified by ELISAs and normalized with the CD81 exosomal marker. Mean exosomal levels of cathepsin D, lysosome-associated membrane protein 1 (LAMP-1), and ubiquitinylated proteins were significantly higher and of heat-shock protein 70 significantly lower for AD than controls in cross-sectional studies (p ≤ 0.0005). Levels of cathepsin D, LAMP-1, and ubiquitinylated protein also were significantly higher for patients with AD than for patients with frontotemporal dementia (p ≤ 0.0...
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.
Developmental Neurobiology, 2019
Down syndrome (DS) is a human genetic disease caused by trisomy of chromosome 21 and characterized by early developmental brain abnormalities. Dysfunctional endosomal pathway in neurons is an early event of DS and Alzheimer's disease. Recently, we have demonstrated that exosome secretion is upregulated in human DS postmortem brains, in the brain of the trisomic mouse model Ts[Rb(12.1716)]2Cje (Ts2) and by DS fibroblasts as compared with disomic controls. High levels of the tetraspanin CD63, a regulator of exosome biogenesis, were observed in DS brains. Partially blocking exosome secretion by DS fibroblasts exacerbated a pre-existing early endosomal pathology. We thus hypothesized that enhanced CD63 expression induces generation of intraluminal vesicles (ILVs) in late endosomes/multivesicular bodies (MVBs), increasing exosome release as an endogenous mechanism to mitigate endosomal abnormalities in DS. Herein, we show a high-resolution electron microscopy analysis of MVBs in neurons of the frontal cortex of 12-month-old Ts2 mice and littermate diploid controls. Our quantitative analysis revealed that Ts2 MVBs are larger, more abundant, and contain a higher number of ILVs per neuron compared to controls. These findings were further corroborated biochemically by Western blot analysis of purified endosomal fractions showing higher levels of ILVs proteins in the same fractions containing endosomal markers in the brain of Accepted Article This article is protected by copyright. All rights reserved. Ts2 mice compared to controls. These data suggest that upregulation of ILVs production may be a key homeostatic mechanism to alleviate endosomal dysregulation via the endosomalexosomal pathway.
Exosomes in the Diseased Brain: First Insights from In vivo Studies
Frontiers in Neuroscience, 2017
Extracellular vesicles (EVs) are nanoscale size vesicles secreted by cells and are important mediators of intercellular communication and genetic exchange. Exosomes, EVs generated in endosomal multivesicular bodies, have been the focus of numerous publications as they have emerged as clinically valuable markers of disease states. Exosomes have been mostly studied from conditioned culture media and body fluids, with the difficulty of isolating exosomes from tissues having delayed their study in vivo. The implementation of a method designed to isolate exosomes from tissues, however, has yielded the first insights into characteristics of exosomes in the brain. It has been observed that brain exosomes from murine models of neurodegenerative diseases and human postmortem brains tend to mirror the protein content of the cells of origin, and interestingly, they are enriched with toxic proteins. Whether this enrichment with neurotoxic proteins is beneficial by relieving neurons of accumulated toxic material or detrimental to the brain by propagating pathogenicity throughout the brain remains to be answered. Here is summarized the first group of studies describing exosomes isolated from brain, results that demonstrate that exosomes in vivo reflect complex multicellular pathogenic processes in neurodegenerative disorders and the brain's response to injury and damage.
The role of exosomes in the processing of proteins associated with neurodegenerative diseases
European Biophysics Journal With Biophysics Letters, 2008
Exosomes are small membranous vesicles secreted by a number of cell types and can be isolated from conditioned cell media or bodily fluids such as urine and plasma. Exosome biogenesis involves the inward budding of multivesicular bodies (MVB) to form intraluminal vesicles (ILV). When fused with the plasma membrane, the MVB releases the vesicles into the extracellular environment as exosomes. Proposed functions of these vesicles include roles in cell–cell signalling, removal of unwanted proteins, and the transfer of pathogens between cells, such as HIV-1. Another such pathogen which exploits this pathway is the prion, the infectious particle responsible for the transmissible neurodegenerative diseases such as Creutzfeldt-Jakob disease (CJD) of humans or bovine spongiform encephalopathy (BSE) of cattle. Interestingly, this work is mirrored by studies on another protein involved in neurodegenerative disease, the amyloid precursor protein (APP) which is associated with Alzheimer’s disease (AD). Recent work has found APP proteolytic fragments in association with exosomes, suggesting a common pathway previously unknown for proteins associated with neurodegenerative diseases. This review will be discussing the current literature regarding the role of exosomes in secretion of the proteins, PrP and APP, and the subsequent implications for neurodegenerative disease.