Exosomes in Parkinson's Disease

Exosomes, nano-sized extracellular vesicles secreted by most cell types, are found in all kinds of biological fluids and tissues, including the central nervous system(CNS). The proposed functions of these vesicles include roles in cell–cell signaling, removal of cellular debris, and transfer of pathogens between cells. Many studies have revealed that exosomes derived from the CNS occur in the cerebrospinal fluid and peripheral body fluids,and their contents are altered during disease, making them an appealing target for biomarker development in Parkinson's disease(PD). Exosomes have been shown to spread toxic a-synuclein(asyn) between cells and induce apoptosis, which suggests a key mechanism underlying the spread of asyn aggregates in the brain and the acceleration of pathology in PD. However, potential neuroprotective roles of exosomes in PD have also been reported. On the treatment side, as drug delivery vehicles, exosomes have been used to deliver small interfering RNAs and catalase to the brain, and have shown clear therapeutic effects in a mouse model of PD. These features of exosomes in PD make them extremely interesting from the point of view of developing novel diagnostic and therapeutic approaches.     

Exosomes and their role in CNS viral infections

Exosomes are small membrane-bound vesicles that carry biological macromolecules from the site of production to target sites either in the microenvironment or at distant sites away from the origin. Exosomal content of cells varies with the cell type that produces them as well as environmental factors that alter the normal state of the cell such as viral infection. Human DNA and RNA viruses alter the composition of host proteins as well as incorporate their own viral proteins and other cargo into the secreted exosomes. While numerous viruses can infect various cell types of the CNS and elicit damaging neuropathologies, few have been studied for their exosomal composition, content, and function on recipient cells. Therefore, there is a pressing need to understand how DNA and RNA viral infections in CNS control exosomal release. Some of the more recent studies including HIV-1, HTLV-1, and EBV-infected B cells indicate that exosomes from these infections contain viral miRNAs, viral transactivators, and a host of cytokines that can control the course of infection. Finally, because exosomes can serve as vehicles for the cellular delivery of proteins and RNA and given that the blood-brain barrier is a formidable challenge in delivering therapeutics to the brain, exosomes may be able to serve as ideal vehicles to deliver protein or RNA-based therapeutics to the brain.     

不明原因的颅内感染与博尔纳病病毒感染的研究

目的分别检测不明原因的颅内感染患者外周血单个核细胞(PBMCs)和脑脊液有核细胞(CSFMCs)中博尔纳病病毒(BDV)p24基因,探讨不明原因颅内感染患者与BDV感染的关系及阳性患者的临床特征。方法用荧光定量巢式逆转录聚合酶链反应(FQ-nRT-PCR)方法检测不明原因颅内感染患者及对照者PBMCs或CSFMCs中BDV p24基因片段,同时用β-肌动蛋白(-βactin)作为内参照,并总结阳性患者的临床特征。结果PBMCs中BDV p24基因片段检测结果显示,实验组7例阳性,对照组均为阴性,差异有统计学意义(P<0.05)。实验组进行CSF检查的32例颅内感染患者中4例外周血和CSF标本BDV p24基因片段检测均为阳性,阳性基因片段产物测序后与BDV标准病毒株V和马源的BDV病毒株H1766序列比较,结果同源性分别为95.35%和98.84%,在4个位点出现基因突变(nt1649 T→C,nt1656 G→A,nt1670 C→T,nt1676 C→T);7例BDV p24基因片段阳性患者主要以精神行为异常为起病方式,患者与动物关系密切,其他临床特征无特殊。结论贵州省遵义市部分不明原因颅内感染的发生与BDV感染有关,主要以精神行为异常为临床特征。     

Exosomes as mediators of neuron-glia communication in neuroinflammation

In recent years,a type of extracellular vesicles named exosomes has emerged that play an important role in intercellular communication under physiological and pathological conditions.These nanovesicles (30–150 nm) contain proteins,RNAs and lipids,and their internalization by bystander cells could alter their normal functions.This review focuses on recent knowledge about exosomes as messengers of neuron-glia communication and their participation in the physiological and pathological functions in the central nervous system.Special emphasis is placed on the role of exosomes under toxic or pathological stimuli within the brain,in which the glial exosomes containing inflammatory molecules are able to communicate with neurons and contribute to the pathogenesis of neuroinflammation and neurodegenerative disorders.Given the small size and characteristics of exosomes,they can cross the blood-brain barrier and be used as biomarkers and diagnosis for brain disorders and neuropathologies.Finally,although the application potential of exosome is still limited,current studies indicate that exosomes represent a promising strategy to gain pathogenic information to identify therapeutically targets and biomarkers for neurological disorders and neuroinflammation.     

Exosomes are released by cultured cortical neurones

Accumulating evidence shows that several cell types have the capacity to secrete membrane proteins by incorporating them into exosomes, which are small lipid vesicles derived from the intralumenal membranes of multivesicular bodies (MVBs) of the endocytic pathway. Exosomes are expelled in the extracellular space upon fusion of the MVB with the plasma membrane. Exosomal release is a way of secreting membrane proteins meant to be discarded, or to be passed on to other cells. Here, we demonstrate, using primary cortical cultures, that neurones and astrocytes can secrete exosomes. We find that exosomes released by cortical neurones contain the L1 cell adhesion molecule, the GPI-anchored prion protein, and the GluR2/3 but not the NR1 subunits of glutamate receptors. We also show that exosomal release is regulated by depolarisation. Our observation suggests that exosomes may have a regulatory function at synapses and could also allow intercellular exchange of membrane proteins within the brain.     

Viral meningitis

Enteroviruses account for 85 to 95% of all cases of aseptic meningitis, but the arboviruses and herpes simplex virus are also important etiologic agents. Mumps, lymphocytic choriomeningitis virus, herpes zoster, human herpesvirus type 6, and influenza viruses are rare causes of meningitis. The virology, pathogenesis, epidemiology, clinical manifestations, diagnostic studies, and established and potential antiviral therapies for viral meningitis are discussed. A differential diagnosis of the aseptic meningitis syndrome is provided.     

Viral encephalitis

Acute viral encephalitis may be caused by a wide range of viruses but the most important is herpes simplex encephalitis (HSE) because of its severity, especially if untreated, and its good response to specific treatment with acyclovir. The outcome of any CNS viral infection is dependent on both the immune status of the host and the virulence of the infecting virus. In evaluating a patient with suspected viral encephalitis there are 3 essential steps, namely the identification of a true parenchymal virus infection of the brain rather than a non–infective encephalopathy, the distinction of an infectious viral encephalitis from an acute disseminated encephalomyelitis (ADEM), and then the determination, where possible, of the specific virus involved. In practice, the precise viral cause of the encephalitis may never be established. Analysis of the CSF for herpes simplex virus (HSV) DNA using the Polymerase Chain Reaction (PCR) has been a significant advance in the diagnosis of HSE as this test has a very high sensitivity and specificity especially with appropriate sample timing. It is essential to commence early treatment with intravenous acyclovir in patients suspected of having HSE because of the remarkable safety and efficacy of this drug and the dangers of delaying potentially effective treatment of life threatening disease. This review outlines the general management approach in patients suspected of having viral encephalitis.     

病毒性脑炎

1 病史摘要 患者,男,18岁,初中肄业.因"眠差,行为异常加重1周,病程3年余",第2次住院.     

Viral antibodies in multiple sclerosis

The sera of 176 MS patients and of 150 healthy adult controls were assayed for antibodies against mumps, rubella, Sendai and herpes simplex viruses, a higher prevalence of measles c.f.a. having already been demonstrated in the MS patients. The CSF of 48 of the MS patients were subjected to the same tests. The patients differed from the controls in a higher prevalence of h.i.a. to mumps and of c.f.a. to herpes simplex. For the latter, but not for the former, the prevalence was statistically higher only in patients treated with immunosuppressants. To date measles seems to be the most seriously incriminated virus in the etiopathogenesis of MS, mumps ranking second.

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Sommario Sono riportiti i risultati delle titolazioni anticorporali verso i virus della parotite, della rosolia, Sendai ed herpes simplex nel siero di 176 pazienti affetti da Sclerosi Multipla e di 150 soggetti sani di controllo, nonché nel liquor di 48 dei malati. In precedenza negli stessi gruppi di soggetti erano stati studiati gli anticorpi antimorbillo. Differenze tra i malati ed i controlli sono state riscontrate solo per la prevalenza nel siero degli anticorpi inibenti l'emoagglutinazione antiparotite e degli anticorpi fissanti il complemento verso l'herpes simplex. Va sottolineato che, al contrario di quanto si è verificato per il virus della parotite, solo i pazienti sottoposti a terapia con farmaci immunodepressivi presentavano una prevalenza degli anticorpi fissanti il complemento verso l'herpes simplex statisticamente maggiore dei controlli. Sulla base delle presenti e di precedenti osservazioni, sembra che il morbillo in primo luogo e la parotite siano i virus per i quali esistono maggiori evidenze di un coinvolgimento nell'eziopatogenesi della Sclerosi Multipla.

     

Exosomes: a novel therapeutic target for Alzheimer's disease?

Extracellular exosomes are formed inside the cytoplasm of cells in compartments known as multivesicular bodies. Thus, exosomes contain cytoplasmic content. Multivesicular bodies fuse with the plasma membrane and release exosomes into the extracellular environment. Comprehensive research suggests that exosomes act as both inflammatory intermediaries and critical inducers of oxidative stress to drive progression of Alzheimer's disease. An important role of exosomes in Alzheimer's disease includes the formation of neurofibrillary tangles and beta-amyloid production, clearance, and accumulation. In addition, exosomes are involved in neuroinflammation and oxidative stress, which both act as triggers for beta-amyloid pathogenesis and tau hyperphosphorylation. Further, it has been shown that exosomes are strongly associated with beta-amyloid clearance. Thus, effective measures for regulating exosome metabolism may be novel drug targets for Alzheimer's disease.