Rethinking the role of ceruloplasmin in brain iron metabolism

For more than three decades, it has been widely accepted that ceruloplasmin plays an important role in iron efflux from mammalian cells, including brain cells, via the activity of ferroxidase. However, in light of recent findings, this view might not be completely accurate and the role of ceruloplasmin in brain iron metabolism may need to be re-evaluated. Based on recent studies, we propose in this article that the role of ceruloplasmin in iron uptake by brain neuronal cells might be more important than its role in iron release from the cells. A possible explanation of why the absence of ceruloplasmin induces excessive iron accumulation in neurons in aceruloplasminemia (ceruloplasmin gene mutations) was also discussed.     

Developmental changes in the expression of iron regulatory proteins and iron transport proteins in the perinatal rat brain

The perinatal brain requires a tightly regulated iron transport system. Iron regulatory proteins (IRPs) 1 and 2 are cytosolic proteins that regulate the stability of mRNA for the two major cellular iron transporters, transferrin receptor (TfR) and divalent metal transporter-1 (DMT-1). We studied the localization of IRPs, their change in expression during perinatal development, and their relationship to TfR and DMT-1 in rat brain between postnatal days (PND) 5 and 15. Twelve-micron frozen coronal sections of fixed brain tissue were obtained from iron-sufficient Sprague-Dawley rat pups on PND 5, 10, and 15, and were visualized at 20 to 1,000x light microscopy for diaminobenzidine activity after incubation with specific primary IRP-1, IRP-2, DMT-1, and TfR antibodies and a universal biotinylated secondary and tertiary antibody system. IRP and transport protein expression increased in parallel over time. IRP1, IRP2, and DMT-1 were partially expressed in the choroid plexus epithelial cells at PND 5 and 10, and fully expressed at PND 15. The cerebral blood vessels and ependymal cells strongly expressed IRP1, IRP2, and DMT-1 as early as PND 5. Substantive TfR staining was not seen in the choroid plexus or ependyma until PND 15. Glial and neuronal expression of IRP1, IRP2, DMT-1, and TfR in cortex, hippocampal subareas and striatum increased over time, but showed variability in cell number and intensity of expression based on brain region, cell type, and age. These developmental changes in IRP and transporter expression suggest potentially different time periods of brain structure vulnerability to iron deficiency or iron overload.     

Increased regional brain concentrations of ceruloplasmin in neurodegenerative disorders

Ceruloplasmin (CP), the major plasma anti-oxidant and copper transport protein, is synthesized in several tissues, including the brain. We compared regional brain concentrations of CP and copper between subjects with Alzheimer's disease (AD, n = 12), Parkinson's disease (PD, n = 14), Huntington's disease (HD, n = 11), progressive supranuclear palsy (PSP, n = 11), young adult normal controls (YC, n = 6) and elderly normal controls (EC, n = 7). Mean CP concentrations were significantly increased vs. EC (P < 0.05) in AD hippocampus, entorhinal cortex, frontal cortex, and putamen, PD hippocampus, frontal, temporal, and parietal cortices, and HD hippocampus, parietal cortex, and substantia nigra. lmmunocytochemical staining for CP in AD hippocampus revealed marked staining within neurons, astrocytes, and neuritic plaques. Increased CP concentrations in brain in these disorders may indicate a localized acute phase-type response and/or a compensatory increase to oxidative stress.     

Sleep and quantitative EEG in neurodegenerative disorders

This paper reviews current knowledge on sleep problems, sleep architecture changes and quantitative EEG alteration brought on by various neurodegenerative diseases, such as Alzheimer's disease (AD), progressive supranuclear palsy (PSP), REM sleep behavior disorder (RBD), Parkinson's disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy MSA, Huntington's disease and Creutzfeldt-Jakob disease, in comparison to normal aging. The study of sleep variables and that of the spectral composition of the EEG can provide valuable information for understanding the pathophysiology and for assisting the diagnosis of neurodegenerative diseases.     

Chemokine receptors in the central nervous system: role in brain inflammation and neurodegenerative diseases

Chemokines were originally described as chemotactic cytokines involved in leukocyte trafficking. Research over the last decade, however, has shown that chemokine receptors are not restricted to leukocytes. In the brain, chemokine receptors are not only found in microglia (a brain macrophage), but also in astrocytes, oligodendrocytes and neurons. In this review, we describe the spatial and cellular distribution of chemokine receptors in the brain, distinguishing between constitutively and inducibly expressed receptors. We then discuss possible physiological functions, including neuronal migration, cell proliferation and synaptic activity. Evidence is emerging that chemokine receptors are also involved in neuronal death and hence neurodegenerative diseases. Chemokines may induce neuronal death either indirectly (e.g. through activation of microglia killing mechanisms) or directly through activation of neuronal chemokine receptors. Disease processes in which chemokines and their receptors are likely to be involved include multiple sclerosis (MS), Alzheimer's disease (AD), HIV-associated dementia (HAD) and cerebral ischemic disease. The study of chemokines and their receptors in the central nervous system (CNS) is not only relevant for the understanding of brain physiology and pathophysiology, but may also lead to the development of targeted treatments for neurodegenerative diseases.     

Review: Iron metabolism and the role of iron in neurodegenerative disorders

Iron plays a role for the biogenesis of two important redox‐reactive prosthetic groups of enzymes, iron sulphur clusters (ISC) and heme. A part of these biosynthetic pathways takes plays in the mitochondria. While several important proteins of cellular iron uptake and storage and of mitochondrial iron metabolism are well‐characterized, limited knowledge exists regarding the mitochondrial iron importers (mitoferrins). A disturbed distribution of iron, hampered Fe‐dependent biosynthetic pathways and eventually oxidative stress resulting from an increased labile iron pool are suggested to play a role in several neurodegenerative diseases. Friedreich's ataxia is associated with mitochondrial iron accumulation and hampered ISC/heme biogenesis due to reduced frataxin expression, thus representing a monogenic mitochondrial disorder, which is clearly elicited solely by a disturbed iron metabolism. Less clear are the controversially discussed impacts of iron dysregulation and iron‐dependent oxidative stress in the most common neurodegenerative disorders, i.e. Alzheimer's disease (AD) and Parkinson's disease (PD). Amyotrophic lateral sclerosis (ALS) may be viewed as a disease offering a better support for a direct link between iron, oxidative stress and regional neurodegeneration. Altogether, despite significant progress in molecular knowledge, the true impact of iron on the sporadic forms of AD, PD and ALS is still uncertain. Here we summarize the current knowledge of iron metabolism disturbances in neurodegenerative disorders.     

Pathogenic contribution of cholesteryl ester accumulation in the brain to neurodegenerative disorders

<正>Cholesteryl esters(CEs) have been increasingly implicated in neurodegenerative disorders such as Alzheimer’s disease(AD).Alois Alzheimer noted three prominent neuropathologic features in his original analysis of the AD brain:senile plaques,neurofibrillary tangles,and lipid granule accumulation.Senile plaques,which are aggregates of amyloid-beta(Aβ),and neurofibrillary tangles,which are aggregates of phosphorylated tau,have been regarded as more consistent characteristics of the AD brain...     

Tau protein isoforms, phosphorylation and role in neurodegenerative disorders

Tau proteins belong to the family of microtubule-associated proteins. They are mainly expressed in neurons where they play an important role in the assembly of tubulin monomers into microtubules to constitute the neuronal microtubules network. Microtubules are involved in maintaining the cell shape and serve as tracks for axonal transport. Tau proteins also establish some links between microtubules and other cytoskeletal elements or proteins. Tau proteins are translated from a single gene located on chromosome 17. Their expression is developmentally regulated by an alternative splicing mechanism and six different isoforms exist in the human adult brain. Tau proteins are the major constituents of intraneuronal and glial fibrillar lesions described in Alzheimer’s disease and numerous neurodegenerative disorders referred to as ‘tauopathies’. Molecular analysis has revealed that an abnormal phosphorylation might be one of the important events in the process leading to their aggregation. Moreover, a specific set of pathological tau proteins exhibiting a typical biochemical pattern, and a different regional and laminar distribution could characterize each of these disorders. Finally, a direct correlation has been established between the progressive involvement of the neocortical areas and the increasing severity of dementia, suggesting that pathological tau proteins are reliable marker of the neurodegenerative process. The recent discovery of tau gene mutations in frontotemporal dementia with parkinsonism linked to chromosome 17 has reinforced the predominant role attributed to tau proteins in the pathogenesis of neurodegenerative disorders, and underlined the fact that distinct sets of tau isoforms expressed in different neuronal populations could lead to different pathologies.     

Abnormal iron accumulation in the brain of neonatal hypotransferrinemic mice

Transferrin is a plasma protein involved in iron delivery to tissues. To study iron transport into the brain under a transferrin deficiency, iron concentration and 59Fe uptake in the brain were measured in neonatal hypotransferrinemic (HP) mice at 7 days of age. Brain iron concentration of the HP mice, in which iron concentration was relatively high in the cerebral cortex and cerebellum, was approximately three times higher than that of non-mutant mice, whereas serum iron concentration of HP mice was significantly lower than that of non-mutant mice. When 59FeCl3 was subcutaneously injected into HP and non-mutant mice, 59Fe was distributed highly in the choroid plexus in the ventricles of HP mice 24 h after injection. The 59Fe distribution in the brain was different between HP and non-mutant mice. On the other hand, the clearance of 59Fe from the blood was very high in HP mice and the hepatic 59Fe concentration of HP mice was more than ten times of that of non-mutant mice. The present findings demonstrate that iron distribution in the brain is changed by transferrin deficiency and that iron abnormally accumulates in the brain of HP mice. It is likely that the management of iron is different in the brain of HP mice.     

经颅超声技术在抑郁症及神经变性疾病伴抑郁中的应用

本文目的是对经颅超声技术(TCS)在抑郁症及神经变性疾病伴抑郁中的应用进行综述,以期为抑郁症及神经变性疾病伴抑郁的临床诊断提供新的方向。TCS在抑郁症患者可表现中缝低回声,在神经变性疾病伴抑郁患者中也出现了特异性表现。本文对TCS在抑郁症及神经变性疾病伴抑郁中的应用进行探讨。     

Insulin receptors and insulin action in the brain: review and clinical implications

Insulin receptors are known to be located on nerve cells in mammalian brain. The binding of insulin to dimerized receptors stimulates specialized transporter proteins that mediate the facilitated influx of glucose. However, neurons possess other mechanisms by which they obtain glucose, including transporters that are not insulin-dependent. Further, insulin receptors are unevenly distributed throughout the brain (with particularly high density in choroid plexus, olfactory bulb and regions of the striatum and cerebral cortex). Such factors imply that insulin, and insulin receptors, might have functions within the central nervous system in addition to those related to the supply of glucose. Indeed, invertebrate insulin-related peptides are synthesized in brain and serve as neurotransmitters or neuromodulators. The present review summarizes the structure, distribution and function of mammalian brain insulin receptors and the possible implications for central nervous system disorders. It is proposed that this is an under-studied subject of investigation.     

The value of CT in diagnosis and prognosis of different inborn neurodegenerative disorders in childhood

Summary Inborn errors of metabolism in 40 children have been investigated by computed tomography to obtain data on the degree of cerebral involvement in neurodegenerative and storage disorders: 20 children had various mucopolysaccharidoses, 8 sphingolipidoses, 3 mucolipidoses, 2 oligosaccharidoses, 3 ceroidlipofuscinoses and 4 had various leucodystrophies. Diagnosis in all patients except Alexander's disease was established by biochemical or histological means.The main findings on CT were cerebral atrophy with enlargement of the ventricles and the subarachnoid spaces and hypodensity of the white matter. The degree of cerebral atrophy seemed to develop according to the age of the patients, as could be seen from the patients with mucopolysaccharidosis III, metachromatic leucodystrophy and GM₁-gangliosidosis. Hypodensity of the white matter was found in mucopolysaccharidosis I-H, II-B, VI, in mucolipidosis II and in patients with leucodystrophies. On the other hand, there was great variability in these CT findings even in siblings, as seen in four patients with mucopolysaccharidosis VI. Among the series there were several patients who did not show any abnormalities in CT, so that a negative CT did not exclude these disorders, even the leucodystrophies. CT features such as cerebral atrophy or hypodensity were helpful in the evaluation of these disorders, though a diagnosis could not be made by CT alone.

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Zusammenfassung Bei 40 Kindern mit verschiedenen angeborenen Stoffwechselstörungen wurde eine craniale Computertomographie durchgeführt, um Aufschluß über das Ausmaß von cerebralen Veränderungen bei neurodegenerativen Leiden und Speicherkrankheiten zu erhalten. Wir untersuchten 20 Kinder mit verschiedenen Mukopolysaccharidosen, 8 mit Sphingolipidosen, 3 mit Mukolipidosen, 2 mit Oligosaccharidosen, 3 mit Ceroidlipofuszinosen und 4 mit seltenen Leukodystrophien. Die Diagnose wurde bei allen Patienten außer bei dem mit M. Alexander biochemisch oder histologisch gesichert.Hirnatrophie und Dichteminderung der weißen Substanz waren die Hauptbefunde bei der CT. Das Ausmaß der Atrophie war bei Patienten mit Mukopolysaccharidose III, metachromatischer Leukodystrophie und GM₁-Gangliosidose altersabhängig. Eine Hypodensität des Marks fand sich bei den Mukopolysaccharidosen I-H, II-B, VI, bei der Mukolipidose II und bei Patienten mit Leukodystrophien. Allerdings sind diese CT-Veränderungen selbst bei Geschwistern inkonstant, wie die Befunde bei 4 Patienten mit Mukopolysaccharidose VI zeigen. Einige Kinder hatten völlig unauffällige Computertomogramme, so daß sich aufgrund eines normalen CT keine der genannten Krankheiten ausschließen läßt.Die gefundenen CT-Veränderungen mit Hirnatrophie und Dichteminderungen der weißen Substanz sind keine spezifischen Befunde der untersuchten Erkrankungen, sie sind jedoch bei den differentialdiagnostischen Überlegungen und zur Verlaufsbestimmung verschiedener Stoffwechselstörungen hilfreich.

     

The DNA repair-ubiquitin-associated HR23 proteins are constituents of neuronal inclusions in specific neurodegenerative disorders without hampering DNA repair

Intracellular inclusions play a profound role in many neurodegenerative diseases. Here, we report that HR23B and HR23A, proteins that are involved in both DNA repair and shuttling proteins to the 26S proteasome for degradation, accumulate in neuronal inclusions in brain from a mouse model for FXTAS, as well as in brain material from HD, SCA3, SCA7, FTDP-17 and PD patients. Interestingly, HR23B did not significantly accumulate in tau-positive aggregates (neurofibrillary tangles) from AD patients while ubiquitin did. The sequestration of HR23 proteins in intracellular inclusions did not cause detectable accumulation of their stable binding partner in DNA repair, XPC. Surprisingly, no reduction in repair capacity was observed in primary human fibroblasts that overexpressed GFP-polyQ, a polypeptide that induces HR23B-positive inclusions in these transfected cells. This illustrates that impairment of the ubiquitin-proteasome system (UPS) by expanded glutamine repeats, including the sequestration of HR23B, is not affecting NER.     

Baicalin and deferoxamine alleviate iron accumulation in different brain regions of Parkinson’s disease rats

Previous studies found that iron accumulates in the substantia nigra of Parkinson’s disease patients. However, it is still unclear whether other brain regions have iron accumulation as well. In this experiment, rats with rotenone-induced Parkinson’s disease were treated by gastric perfusion of baicalin or intraperitoneal injection of deferoxamine. Immunohistochemical staining demonstrated that iron accumulated not only in the substantia nigra pars compacta, but also significantly in the striatum globus pallidus, the dentate gyrus granular layer of the hippocampus, the dentate-interpositus and the facial nucleus of the cerebellum. Both baicalin and deferoxamine, which are iron chelating agents, significantly inhibited iron deposition in these brain areas, and substantially reduced the loss of tyrosine hydroxylase-positive cells. These chelators also reduced iron content in the substantia nigra. In addition to the substantia nigra, iron deposition was observed in other brain regions as well. Both baicalin and deferoxamine significantly inhibited iron accumulation in different brain regions, and had a protective effect on dopaminergic neurons.     

Therapeutic applications of chelating drugs in iron metabolic disorders of the brain and retina

Iron is essential for normal cellular function, however, excessive accumulation of iron in neural tissue has been implicated in both cortical and retinal diseases. The exact role of iron in the pathogenesis of neurodegenerative disorders remains incompletely understood. However, iron-induced damage to the brain and retina is often attributed to the redox ability of iron to generate dangerous free radicals, which exacerbates local oxidative stress and neuronal damage. Iron chelators are compounds designed to scavenge labile iron, aiding to regulate iron bioavailability. Recently there has been growing interest in the application of chelating agents for treatment of diseases including neurodegenerative conditions, characterized by increased oxidative stress. This article reviews both clinical and preclinical evidence relating to the effectiveness of iron chelation therapy in conditions of iron dyshomeostasis linked to neurodegeneration in the brain and retina. The limitations as well as future opportunities iron chelation therapy are discussed.