Advances in treatment of neurodegenerative diseases: Perspectives for combination of stem cells with neurotrophic factors

Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis, are a group of incurable neurological disorders, characterized by the chronic progressive loss of different neuronal subtypes. However, despite its increasing prevalence among the ever-increasing aging population, little progress has been made in the coincident immense efforts towards development of therapeutic agents. Research interest has recently turned towards stem cells including stem cells-derived exosomes, neurotrophic factors, and their combination as potential therapeutic agents in neurodegenerative diseases. In this review, we summarize the progress in therapeutic strategies based on stem cells combined with neurotrophic factors and mesenchymal stem cells-derived exosomes for neurodegenerative diseases, with an emphasis on the combination therapy.     

Oxysterols and neurodegenerative diseases

In contrast to their parent molecule cholesterol, two of its side-chain oxidized metabolites are able to cross the blood–brain barrier. There is a concentration-driven flux of 24S-hydroxycholesterol (24S-OHC) from the brain into the circulation, which is of major importance for elimination of excess cholesterol from the brain. The opposite flux of 27-hydroxycholesterol (27-OHC) from the circulation into the brain may regulate a number of key enzymes within the brain. In vitro experiments suggest that the balance between the levels of these two molecules may be of importance for the generation of β-amyloid peptides. In primary cultures of rat hippocampal cells 27-OHC is able to suppress expression of the activity regulated cytoskeleton-associated protein (Arc), a protein important in memory consolidation which is reduced in patients with Alzheimer’s disease (AD). In the present work we explore the possibility that the flux of 27-OHC from the circulation into the brain represents the missing link between AD and hypercholesterolemia, and discuss the possibility that modification of this flux may be a therapeutic strategy. Lastly, we discuss the use of oxysterols as diagnostic markers in neurodegenerative disease.     

Oligodendrocytes in neurodegenerative diseases

Oligodendrocyte is a highly specialized glial cell type in the vertebrate central nervous system, which guarantees the long-distance transmission of action potential by producing myelin sheath wrapping adjacent axons. Disrupted myelin and oligodendrocytes are hallmarks of some devastating neurological diseases, such as multiple sclerosis, although their contribution to neurodegeneration in a given disease is still controversial. However, accumulating evidence from clinical studies and genetic animal models implicates oligodendrocyte dysfunction as one of major events in the processes of initiation and progression of neurodegeneration. In this article, we will review recent progress in understanding non-traditional function of oligodendrocytes in neuronal support and protection independent of myelin sheath and its possible contribution to neurodegeneration. Oligodendrocytes play a pivotal role in neurodegenerative diseases among which special emphasis is given to multiple system atrophy and Alzheimer’s disease in this review.     

Proteomics in neurodegenerative diseases

The effects of amyloid-beta (Aβ) protein on the expression of m1, m2 subunits of mAChR and on α7nAChR were analyzed in the cerebral cortex and in the hippocampus of rats following injections of Aβ (1–40) (BACHEM, 2 μg in 1 μL of PBS) into the left retroesplenial cortex (RSg) and injections of 1 μL of PBS into the right RSg. Sections were immunoreacted for the localization of α7, m1, m2, GABA, somatostatin and parvalbumin. Injections of Aβ resulted in loss of neurones expressing α7- and m1-like immunoreactivity (IR) in frontal, RSg cortices, hippocampus and subicular complex. A decrease of α7, m1- and m2-like-IR fibers and structures-like terminals was also seen in hippocampus, subicular and cerebral cortex. α7nAChR and m1, m2 subuntis of mAChRs were most commonly identified on GABAergic interneurones. These results point to an effect of Aβ on the synthesis of α7nAChR and mAChRs and suggest an important role of cholinoceptive interneurones in the dysfunction of hippocampus and cerebral cortex seen in AD.     

硫氧还蛋白与神经退行性病变

神经退行性病变与胞内氧化还原失衡诱发的神经元损伤,死亡有密切关系,硫氧还原白参与维持胞内氧化还原平衡,在氧化应激中起重要的氧还调节作用,因此成为对抗神经退行性病变的重要蛋白之一。硫氧还蛋白可能通过激活某些有氧还调节功能的酶,清除自由基和调节细胞内分子通道等发挥对神经元的保护作用,对转基因动物的研究,进一步提示硫氧还蛋白在神经退行性病变的防治中可能发挥重要作用。     

Prions and neurodegenerative diseases

The long-term, progressive decay of the central nervous system typifies prion diseases, a group of rare, transmissible maladies affecting humans, sheep, cattle and some other types of mammal. Little is known about the early molecular events in its pathogenesis but the diverse roles of PrP, the prion protein, in its destructive action have recently been re-emphasised.     

Expression of Ext1, Ext2, and heparanase genes in brain of senescence-accelerated OXYS rats in early ontogenesis and during development of neurodegenerative changes

Heparan sulfate (HS) and heparan sulfate proteoglycans (HSPG) play a significant role in brain development, and their structural and quantitative changes are revealed during aging and in neurodegenerative disorders. The mechanism of these changes is not clear, but is likely to be associated with alteration in the expression and/or activity of enzymes responsible for HSPG biosynthesis and degradation. The contents of mRNAs of the genes Ext1 and Ext2 encoding polymerization enzymes and of gene Hpse of heparanase degrading HS were determined in the brain of prematurely aging OXYS rats during early postnatal development and during appearance of signs of brain accelerated aging (at age of 1, 7, 14, 30, 60, and 420 days). Wistar rats of the same age were used as controls. Expression levels of the genes Ext1, Ext2, and Hpse in the brain of rats of both strains were maximal during the two first weeks of life, and the contents of mRNAs of all genes in the brain of newborn and 7-day-old OXYS rats were significantly higher than in Wistar rats. By the 14th day of life the differences leveled, but at the age of 30 days on the background of a decrease in the contents of mRNAs of Ext1, Ext2, and Hpse in OXYS rats they became more pronounced (three-, four-, and twofold, respectively). Differences between the strains were absent at the age of 60 days and 14 months, and expression of all the genes was significantly lower than in the newborn animals. A strong positive correlation was found between contents of mRNAs of all the studied genes, and this suggested that heparanase should be involved in HSPG metabolism together with Ext1 and Ext2. Based on these and earlier findings, we conclude that development of the OXYS rat brain occurs on the background of significant alterations in HSPG metabolism that precede the development of neurodegenerative manifestations recently detected by magnetic resonance imaging.     

副监护子CHIP与神经退行性疾病

CHIP属于连接酶类,具有E3泛素连接酶活性,参与能量代谢途径和新陈代谢。包括阿尔茨海默病(Alzheimer'sdisease,AD)、帕金森病(Parkinson'sdisease,PD)、亨廷顿病(Huntington'sdisease,HD)等在内的神经退行性疾病的主要病理学特征之一——细胞中异常蛋白的聚集,如tau蛋白和α-突触核蛋白等,副监护子CHIP与分子伴侣,如Hsc70/Hsp70、Hsp90等相互作用对这些异常蛋白的产生具有调节作用。最近研究表明,CHIP改变了Hsc70和Hsp90介导调节的信号通路中蛋白折叠和降解的平衡,参与细胞内蛋白质的质量控制;Hsp70/CHIP伴侣系统在tau蛋白生物学和tau蛋白病理学机制中具有重要作用;CHIP可以作为α-突触核蛋白蛋白酶体降解途径和溶酶体降解途径的分子开关。这些研究进展对于进一步揭示神经退行性疾病的发病机制和研制新一代治疗药物具有重要的作用。     

ER stress and neurodegenerative diseases

Endoplasmic reticulum (ER) stress is caused by disturbances in the structure and function of the ER with the accumulation of misfolded proteins and alterations in the calcium homeostasis. The ER response is characterized by changes in specific proteins, causing translational attenuation, induction of ER chaperones and degradation of misfolded proteins. In case of prolonged or aggravated ER stress, cellular signals leading to cell death are activated. ER stress has been suggested to be involved in some human neuronal diseases, such as Parkinson's disease, Alzheimer's and prion disease, as well as other disorders. The exact contributions to and casual effects of ER stress in the various disease processes, however, are not known. Here we will discuss the possible role of ER stress in neurodegenerative diseases, and highlight current knowledge in this field that may reveal novel insight into disease mechanisms and help to design better therapies for these disorders.     

SIRT1与神经变性疾病

SIRT1(silent mating type information regulation2homolog1)是Sirtuins脱乙酰基酶家族中的一员,是酵母沉默信息调节因子SIR2(silence information regulator)的同源物,因其能在许多生物体模型中作为寿命延长调节子调控细胞生命周期而受到特别关注。SIRT1蛋白存在于哺乳动物细胞质和细胞核中,是老化相关蛋白。SIRT1作用于基因转录因子能加强基因组的稳定性。神经系统发生变性疾病时SIRT1表达量上调,起到一定的神经保护作用。但有实验验证神经元损伤SIRT1过表达导致记忆缺失,并没有起到神经保护作用。SIRT1诱导剂,可以是Sirtuin的激动剂也可以是能量限制状态。目前在生命科学领域里SIRT1已经凸显其科学价值地位,该文就SIRT1及其与神经变性疾病之间的关系做一综述。     

Vitamin E and neurodegenerative diseases

Vitamin E is essential for neurological function. This fact, together with a growing body of evidence indicating that neurodegenerative processes are associated with oxidative stress, lead to the convincing idea that several neurological disorders may be prevented and/or cured by the antioxidant properties of vitamin E.

In this review, some aspects related to the role of vitamin E against Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and ataxia with vitamin E deficiency will be presented.     

Stem cells and neurodegenerative diseases

Neurodegenerative diseases are characterized by the neurodegenerative changes or apoptosis of neurons involved in networks, which are important to specific physiological functions. With the de-velopment of old-aging society, the incidence of neurodegenerative diseases is on the increase. How-ever, it is difficult to diagnose for most of neurodegenerative diseases. At present, there are too few effective therapies. Advances in stem cell biology have raised the hope and possibility for the therapy of neurodegenerative diseases. Recently, stem cells have been widely attempted to treat neurodegen-erative diseases of animal model. Here we review the progress and prospects of various stem cells, including embryonic stem cells, mesenchymal stem cell and neural stem cells and so on, for the treatments of neurodegenerative diseases, such as Parkinson’s disease, Alzheimer’s disease, Hunt-ington’s disease and Amyotrophic lateral sclerosis/Lou Gehrig’s disease.     

空气污染与神经退行性疾病

随着现代社会工业的发展,空气污染日益严重,空气污染对人体的损害也越来越大。空气污染中的有害物质,能通过各种途径引起各系统的疾病,甚至会影响儿童的身体和智力发育。研究发现,长期暴露或急性暴露在某些空气污染物中可以直接损伤中枢神经系统,或污染物引起呼吸系统和免疫系统等产生有害因子,通过外周循环到达大脑,导致大脑的神经炎症、神经毒性、氧化应激等反应,最终产生神经退行性病变,如阿尔茨海默病（Alzheimer’s disease,AD）、帕金森病（Parkinson’s disease,PD）等。