Importantly, hGH also induces the expression of a number of neurotrophic factors (IGF- I, EGF and its receptor, EPO, VEGF, NGF) (Figure 1) and increases the cerebral metabolic turnover of NA (Noradrenaline) and DA (Dopamine) [360, 367-372]. While wit is known that neural progenitors are produced at the cerebral level in different neurogenic niches along the whole life, their production also progressively decreases as the subject ages. It remains to be established whether the effect of hGH administration might compensate this physiological age-related decrease production and/output of different human growth factors (HGF), neural-derived or otherwise, but preliminary results from our group indicate that this occurs  . While the neurotrophic effect of hGH, either exerted by itself or by inducing the expression of a number of neurotrophic factors is now clear (Figure 1), no long ago it seemed that this effect was exerted only after a traumatic brain injury (TBI) or after a stroke or in children with cerebral palsy, when suffering GH-deficiency as a result of the brain insult. However, the positive effects played by GH on brain repair after an injury have been also demonstrated in TBI patients without GH-deficiency [374, 375]. In spite that hGH concentrations are low in the cerebrospinal fluid of patients with Amyotrophic Lateral Sclerosis (ALS), a clinical trial demonstrated that hGH administration exerted no effect in the clinical progression of this fatal neurodegenerative disease [375, 376]. However, studies in vitro and in animal models of ALS demonstrated that GH administration played a protective effect on mutant SOD-1-expressing motor neurons, increasing the survival time and improving motor performance and weight loss of GH-treated transgenic mice . On the other hand, it has been shown that in animal models the intra-hippocampal injection of the hormone improves spatial cognition  as well as learning and memory in AD- like rats . Therefore, a possible usefulness of hGH in AD has been recently postulated . It is possible that the time at which hGH administration is given in relation to the development of AD may play a significant role in the results obtained. In fact, GH has been shown to prevent age-induced reduction in the expression of some components in rats, including cytochromes b and c of the mitochondrial respiratory chain [381, 382].
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Oftentimes bioinformatics tools beyond protein database search engines are needed to turn the enormous amount of data into useful information. For example, surface enhanced laser desorption ionization mass spectrometry (SELDI-MS) is one of the few methods that can be used to profile several hundred proteins from complex samples with a reasonable throughput. However, SELDI-MS profiles are characterized by complex spectra, high dimensionality, and significant noise, which all together make the discovery of biomarker peaks in clinical samples a challenging task. The need for computational methods is obvious in order to find peaks that correlate with phenotypes and to assess their statistical significance. Several classification techniques have been utilized for discriminating cancer samples from control samples using proteomic data. The two main components of these approaches are the feature selection method and a classification method to build a predictive model . For example, Li et al used the signal-to-noise ratio for an initial feature selection and subsequently used “unified maximum separability analysis” repeatedly for classification in their breast cancer study .
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significantly reduced by 10%. These associations are obscured when total stroke is evaluated as the outcome. Many large randomized controlled trials investigating the effect of Vitamin E on incident major cardiovascular events were performed during the past two decades, but most did not find an overall significant effect. Likewise, two recent meta-analyses did not find an effect on mor- tality from all causes, cardiovascular death, and stroke from all causes . The Alpha Tocopherol, Beta Caro- tene Cancer Prevention trial was the first, showing that in male smokers 50 mg/day of Vitamin E increased the risk of hemorrhagic stroke. This result was confirmed in the Physicians’ Health Study II, which randomized 14,641 male physicians from the United States to 400 I.U. Vita- min E on alternate days or placebo. Results from the Women’s Health Study, which randomized 39,876 ap- parently healthy women to 600 I.U. Vitamin E on alternate days or placebo, however, do not indicate increased risk of hemorrhagic stroke in women . In this meta-ana- lysis of randomized trials, we found that Vitamin E in- creased the risk for hemorrhagic stroke by 22% and re- duced the risk of ischemic stroke by 10%. Using total stroke as the outcome obscures these harms and benefits. However, given the relatively small reduction in risk of ischemic stroke and the generally more severe outcome of hemorrhagic stroke, indiscriminate widespread use of Vitamin E should be cautioned against .
disease and to their mechanisms of aggregation and tox- icity. The effects of such drugs are hard to predict, how- ever. For example, the induction of the heat shock response actually exacerbates Htt IB formation in a cel- lular model of HD . In addition, it has been pointed out that, under normal physiological conditions, the heat shock response and other proteotoxic stress response pathways are activated only transiently, and that multiple cellular mechanisms are in place to limit and down- regulate these responses . Consistent with those facts, an Hsp90 inhibitor that induces the heat shock response in HD model mice was found to provide short- term beneficial effects, but those benefits proved transient . Yet another potential issue with HSF1 activators is that HSF1 promotes tumorigenesis and is activated in a broad range of highly malignant human cancers [113, 114]. This issue is not necessarily unsurmountable, however, as it has also been shown that the HSF1 drives a different tran- scriptional program and stimulates different sets of cellular processes in cancer cells (including proliferation, invasion, and metastasis) than it does in normal cells . The ability of HSF1 to activate distinct transcriptional pro- grams in cancer cells versus normal cells is thought to result in part from differences in post- transcriptional modifications to HSF1 in the different cell types [113, 114], which in turn raises the possibil- ity that the neuroprotective effects of HSF1 could be harnessed separately from its tumorigenic ones.
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discussion on three genes, GPATCH2L, UHRF1BP1L, and VPS13C, for which we discovered additional genetic evidence consistent with replication in independent cohorts. In the IPDGC cohort, a single PD case was identified with a homozygous stopgain variant (p.R362X) in GPATCH2L and a second individual with the identi- cal, rare genotype was discovered in PPMI. This variant is reported with a low frequency of 0.003% in ExAC. Although minimal clinical or demographic information is available within ExAC, this finding is compatible with population prevalence estimates for PD . Neverthe- less, genotyping of p.R362X in additional large PD case and control cohorts will be required to definitively estab- lish an association with PD susceptibility. GPATCH2L knockdown both increased mitochondrial roundness and impaired Parkin translocation. The encoded protein, GPATCH2L, which has not previously been studied, contains a glycine-rich RNA-binding motif, the “G- patch” domain . GPATCH2, a paralog of GPATCH2L, is upregulated in cancer cells, localizes to the nucleus where it interacts with RNA-processing machinery, and manipulation in culture alters cell proliferation [58, 59]. Notably, GPATCH2L is non-conserved in either the C. ele- gans or Drosophila genomes, precluding study of this can- didate in these models. While our results using cellular assays implicate GPATCH2L in mitochondrial quality con- trol mechanisms, further follow-up studies in mammalian model systems will be needed to confirm a role in PD pathogenesis.
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In addition to brain region-specific emergence of α-syn strains, different strains of α-syn aggregates could also underlie the tremendous heterogeneity of synucleinopathies among different individuals (Halliday et al., 2011). While mostly found in the neurites and neuronal cell bodies for the majority of synucleinopathies, α-syn inclusions are largely confined to oligodendrocytes in multiple system atrophy (Tu et al., 1998), which could be caused by a unique strain of pathological α-syn developing predominantly in oligodendrocytes but rarely in neurons. PDD and DLB, belonging to a continuum of LB diseases, are clinically stratified according to the interval between the onset of motor symptoms and that of cognitive deficits which can vary by decades (Ballard et al., 2006; McKeith, 2006; Tsuboi and Dickson, 2005). While co-morbid AD pathologies are more common in DLB than in PDD, a bimodal distribution of neocortical NFTs has been found in DLB cases (Gearing et al., 1999). Furthermore, several studies have suggested the existence of two subgroups of PDD patients, one group with younger onset, long motor-dementia interval and relatively long disease duration, and the other group with older onset, short motor-dementia interval and more malignant disease course (Compta et al., 2011; Halliday et al., 2008; Jellinger et al., 2002). Interestingly, the former usually presents purely LB pathologies, but the latter most often shows concomitant AD pathologies. Although co-morbid AD pathologies in PDD and DLB may develop independently from LB pathologies, our study raises the possibility that AD pathologies, especially NFTs, could be directly but variably induced by different strains of pathological α-syn, the underlying substrates for the vast clinical variations of synucleinopathies.
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The objective of this review is to do an overview about the current knowledge of Anti Iglon5 Syndrome, a disease that was first described in 2014. The IgLON proteins are a family of cell adhesion molecules and the presence of antibodies against IgLON5 are crucial for diagnosis of Anti IgLON5 Syndrome. This syndrome has an expanded clinical spectrum that involves prominent sleep disorder, progressive bulbar dysfunction, gait instability with abnormal eye movements reminiscent and cognitive deterioration sometimes associated with chorea. The main neuropathological finding is the neuronal loss with hyperphosphorylated tau (p-Tau) protein accumulation at hypothalamus, brainstem tegmentum, hippocampus, periaqueductal gray matter, medulla oblongata and upper cervical cord. The exact pathogenesis is still unclear and involves a neurodegenerative process and autoimmune response. The early diagnosis is
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diseases (Prusiner, 1994). Several hypotheses about the nature of the infectious agent have been proposed. Initially, the agent was thought to be a slow virus (Sigurdsson, 1954; Thormar, 1971) because of several criteria: a long incubation period of month to decades until the onset of disease, limitation of the infection to a single host and pathoanatomical changes in a single organ or tissue. Further research revealed that the agent differed substantially from viruses and was extremely resistant to ultraviolett and ionizing radiation and treatment with nucleases. Such findings led to the suggestion that the transmissible agent may be devoid of nucleic acid (Alper et al., 1967). In 1967, J.S.Griffith postulated the hypothesis that the causative agent might be a protein (Griffith, 1967). The theory of a self-propagating proteinaceous agent (Prusiner, 1982) was proposed after the isolation of a protease- resistant sialoglycoprotein specifically associated with infectivity, designated the prion protein (PrP) (Bolton et al., 1982). The term prion, which was devised by Stanley Prusiner, is the abbreviation for “proteinaceous infectious particle” and was defined as “small proteinaceous infectious particle that resists inactivation by procedures which modify nucleic acids” (Prusiner, 1982).
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to neuronal function including the regulation of calcium homeostasis, phospholipid synthesis and exchange, mito- chondrial biogenesis and dynamics and apoptosis. It is in- teresting that disturbance in MERC are involved in most of the neurodegenerative diseases studied such as AD, PD and ALS as discussed above. Indeed, disturbance in MERC provides a connection for the various seemingly disparate features of these neurodegenerative diseases which may suggest that the disturbance in MERC may serve as a common convergent mechanism underlying neurodegeneration. Admittedly appealing, this hypothesis faces several challenges. First, the many conflicting obser- vations, likely due to the different methods used, need to be reconciled. For example, the fundamental involvement of Mfn2 in the ER-mitochondria tethering is under hot de- bate and the effects of PS2 on MAM need clarification. Secondly, it appears that both upregulated and disrupted MAM functions are implicated in neurodegenerative dis- eases, even in the same disease. For example, VAPB-P56S mutant caused enhanced ER-mitochondria crosstalk while TDP43 and FUS disrupted ER-mitochondria contacts. While both upregulated and disrupted MAM function could lead to cellular dysfunction and neurodegeneration, this highlights the need to characterize the effects of specific neurodegenerative disease insults on the ER– mitochondria axis. Thirdly, the detailed mechanism of MAM disturbance in these conditions needs to be worked out. Is there a common mechanism? TDP43 and FUS disrupt the VAPB-PTPIP51 tethering through GSK3β activation. While GSK3β is activated in many of these neurodegenerative diseases, it may not elicit the same out- come since PS1 mutation caused GSK3β activation  but led to increased ER-mitochondria tethering . Fun- damentally, therefore, the pathophysiological relevance of these observations also need to be firmly established.
While peripheral immune access to the central nervous system (CNS) is restricted and tightly controlled, the CNS is capable of dynamic immune and inflammatory responses to a variety of insults. Infections, trauma, stroke, toxins and other stimuli are capable of producing an immediate and short lived activation of the innate immune system within the CNS. This acute neuroinflammatory response includes activation of the resident immune cells (microglia) resulting in a phagocytic phenotype and the release of inflammatory mediators such as cytokines and chemokines. While an acute insult may trigger oxidative and nitrosative stress, it is typically short- lived and unlikely to be detrimental to long-term neuronal survival. In contrast, chronic neuroinflammation is a long-standing and often self-perpetuating neuroinflammatory response that persists long after an initial injury or insult. Chronic neuroinflammation includes not only long- standing activation of microglia and subsequent sustained release of inflammatory mediators, but also the resulting increased oxidative and nitrosative stress. The sustained release of inflammatory mediators works to perpetuate the inflammatory cycle, activating additional microglia, promoting their proliferation, and resulting in further release of inflammatory factors. Neurodegenerative CNS disorders, including multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), tauopathies, and age-related macular degeneration (ARMD), are associated with chronic neuroinflammation and elevated levels of several cytokines. Here we review the hallmarks of acute and chronic inflammatory responses in the CNS, the reasons why microglial activation represents a convergence point for diverse stimuli that may promote or compromise neuronal survival, and the epidemiologic, pharmacologic and genetic evidence implicating neuroinflammation in the pathophysiology of several neurodegenerative diseases.
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these studies need to be furthered in animal models, with the goal of testing both Hsp90 inhibitors efficacy in improving neuro-pathology and their safety under long- term administration schedules. While several of the stud- ies have used GM and its derivatives, these agents have several liabilities that limit their future clinical use . Development for cancers of Hsp90 inhibitors of scaffolds distinct from that of GM is currently reaching an explo- sive phase, where several agents are in clinical evaluation, with many others following behind . It is likely that the Hsp90 inhibitor classes with best safety profiles will also move into the neurodegenerative space. It now remains the goal of medicinal chemistry to deliver CNS- permeable Hsp90 inhibitors with a good therapeutic index to fulfill the promise of these agents in the treat- ment of neurodegenerative diseases.
Secondary metabolites in plants including phenol, terpenes and various other plant extracts exert the action of antioxidant. [7,8,9,10] Throughout the world plants are analysed for its medicinal properties, low toxicity and its economic values.  It has been reported that diet rich with fresh fruits and vegetables reduce the chances of cardiovascular diseases and certain forms of cancer.  Rasayana and Ayurveda the Indian traditional system of medicines have used several plants for the treatment of number of diseases. 
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structures that maintain the cerebral microenvironment. The first layer of protection that prevents serum proteins from entering the brain is formed by several unique tight-junction proteins, which are susceptible to proteolysis by the MMPs. Other layers beyond the endothelial cells include the basal lamina, the pericytes, and astrocyte endfeet; these compo- nents form the neurovascular unit (NVU). The major brain diseases involving the MMPs are stroke, multiple sclerosis (MS), and dementia; in each of these disorders, the MMPs are a key factor in the neuroinflammatory response. The focus of this review will be selectively on the role of the MMPs in the pathological changes in the blood vessels during various injuries. Several earlier reviews describe additional roles of the MMPs. 6–10
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Prion diseases are transmissible protein misfolding dis- orders in which misfolding of a host-encoded prion pro- tein (PrP) occurs. PrP is a 253 amino acids (aa) protein. The first 22 N-terminal aa are removed from PrP after its transport to endoplasmic reticulum, while the last 23 C-terminal aa are cleaved off after the addition of glyco- sylphosphatidylinositol (GPI) anchor, which helps the protein to attach to the outer surface of cell membranes. PrP may exist in two forms: a normal cellular prion pro- tein designated as PrP C and a pathogenic misfolded con- former designated as PrP Sc . Both PrP C and PrP Sc conformers are encoded from the same sequence of the 16 kb single copy PRNP gene that is positioned on the short (p) arm of human chromosome 20 (20p13), from base pairs 4,666,796-4,682,233. The human PRNP con- tains two exons with the second one carrying the whole open reading frame. The abnormal PrP Sc isoform differs from the normal PrP C isoform in secondary and tertiary structure, but not in primary amino acids sequence. PrP C is predominantly rich in alpha helical contents, while PrP Sc is predominantly rich in beta sheet contents [1-5]. This conformational discrepancy renders the
Scrapie is the ancient form of TSEs. It is known since 1732 and has occurred in sheep, goats and moufflons . As is the case with other prion diseases, clinico- pathological phenotypes of scrapie vary according to the prion strain and animals ’ genetic background. Multiple prion strains may exist in a single scrapie isolate and a PrP Sc conformer underrepresented in one breed may be selected as dominantly propagating strain in another breed [4,5]. Clinical symptoms may include behavioral changes, blindness, ataxia, incoordination, hyperexitabil- ity and tremors. Intense pruritus is the most common symptom which usually leads to wool loss by rubbing and scraping, and results in a characteristic nibbling response from animal when the dorsum is scratched or pressure over the base of tail is applied. The incubation period of scrapie is 2-5 years and death occurs within 2 weeks to 6 months after clinical onset. Neuropathologi- cal signs are spongiform vacuolation, astrogliosis and the deposition of PrP Sc amyloid plaques in the central nervous system (CNS). PrP Sc has been detected in the nervous system, tonsils, spleen, lymph nodes, nicitating
ii) NeuroGeM allows easy identification (by non computational experts) of genes that modify the neurodegenerative toxicity in several ND models. Hence, cross-disease comparisons can identify potential generic modifiers that then can be tested experimentally in other disease models in other organisms (rodents) or compared to human genetic data. A first search for generic modifiers revealed that the genes DnaJ-1, thread, Atx2, and mub are modifiers in 5 out of 7 ND models in D. melanogaster (Figure 4c). Interestingly, DNAJB4 and BIRC3, the mammalian orthologs of DnaJ-1 and thread, have recently been shown to reduce neuronal cell death when up-regulated in multiple mammalian ND
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Usually, embryonic midbrain neurons from embryonic day 14 (E14) are dissected  a high yield of dopaminergic neurons can be obtained, which can be exposed to various neurodegenerative stimuli. Several neurotoxins are employed to study neurodegeneration. In particular, 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenylpyridinium (MPP+) are widely accepted to induce neurotoxicity. Both neurotoxins are thought to induce dopaminergic toxicity by intra- and extra cellular oxidation, hydrogen peroxide formation, and direct inhibition of the mitochondrial respiratory chain . On the one hand, this cell model is very suitable to study methods of neurodegeneration and neurite retraction; on the other hand, possible neurorestorative capacities by pharmacological compounds and the underlying mechanisms can be nicely illustrated in figure 4.
Physiological tau is a phosphoprotein which stabilizes the microtubules. In the brain, six isoforms of tau exist with either three repeats (3R) or four repeats (4R) of the mi- crotubules-binding domain (Buée et al. 2000). Aggregated tau proteins consist of post- translationally modified tau isoforms, whereby specific phenotypes/neurodegenerative diseases are associated with specific tau deposits that differ in microscopic appearance and ultrastructure (Buée et al. 2000; Villemagne et al. 2015). Importantly, the same clinical tauopathy phenotype can be caused by different misfolded tau proteins and vice-versa (Villemagne et al. 2015). In general, aggregated tau proteins are mainly lo- cated intracellularly and therefore a complex target for PET imaging. Current tau radiotracers share β -sheet binding properties. Since other misfolded proteins have simi- lar structures, high selectivity for aggregated tau proteins is necessary (Lois et al. 2018). This is of particular interest, as tau aggregates can be co-localized to Aβ plaques with much higher concentrations of A β plaques compared to tau deposits (Villemagne et al. 2015). First-generation tau PET radiotracers – [ 18 F]AV-1451, [ 11 C]PBB3, [ 18 F]THK5351 (Fig. 8) – showed favourable kinetics and high affinity to the 3R/4R tau isoform com- bination which is typical in AD (Villemagne et al. 2015; Lois et al. 2018; Villemagne 2018). However, the limitation of the first-generation tau PET radiotracers are a
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Several epidemiologic studies suggested the presence of circadian disturbances at the preclinical stage of ADRD. CRD might be considered as a useful preclinical marker or prodromal for neurodegenerative diseases and help with the early detection of the disease. Emerging evidence from longitudinal studies also showed that CRD precedes the development of ADRD or PD. Additional confirmatory studies with longer follow-up are needed to examine the relationship between different circadian markers and subsequent risk of developing neurodegenerative diseases, and should consider the use of biomarkers to help understand potential mechanisms. For example, using structural MRI or PET scans of the brain and examining longitudinal changes in CSF Aβ and tau levels will help clarify if circadian disturbances might contribute to AD pathology or structural change in the brain. Studies of biological mechanisms and intervention trials are required to determine if CRD is a cause of neurodegenerative diseases.
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Alzheimer disease (AD) is the most common cause of se- nile dementia and is characterized by progressive dementia accompanied by personality changes, psychosis, and lan- guage problems. Neuropathology is characterized mainly by extracellular senile plaques, consisting primarily of β- amyloid (Aβ), and intracellular neurofibrillary tangles, with hyperphosphorylated microtubule associated protein tau as a main constituent. Dystrophic neurites surrounding the plaques are ubiquitinated and consist of several ubiquitin-binding proteins, such as UBQLNs and SQSTM1/p62. There is not much evidence that the UPS is involved in degradation of Aβ or its precursor, the β- amyloid precursor protein (βAPP). On the other hand, tau is inefficiently degraded by the UPS, although the non- canonical 20S proteasomal degradation rather than the ubiquitin-dependent 26S proteasomal degradation seems to have a predominant role . Despite the limited role for the UPS in the recycling of Aβ and tau, there is evi- dence that both of these proteins can impair UPS function [26,27] and such impairments have been observed in sev- eral brain regions of patients with AD . Interestingly, a frame-shift mutant of ubiquitin B (UBB +1 ) has been found to accumulate in the dystrophic neurites and neurofibril- lary tangles of AD  as well as other tauopathies and in polyglutamine diseases but not in synucleinopathies . Although low levels of UBB +1 are degraded by the UPS, high levels of UBB +1 are incompletely degraded by the UPS, resulting in inhibition . It has been reported that ubiquitination of UBB +1 is mediated by E2-25 K, which is