Iron in neurodegenerative disorders

Increasing evidence implicates a role of iron in the pathogenesis of numerous neurodegenerative diseases due to its capacity to enhance production of toxic reactive radicals and to induce protein aggregation. The underlying mechanism of iron accumulation in areas of the brain specific for the respective disease, however, is still unknown. Recent molecular and biochemical studies provide new insights into the consequences of impairment of brain iron metabolism. This review summarizes our understanding of the regulation of iron in the brain and defines the current knowledge on the involvement of iron metabolism in neurodegenerative diseases with genetically determined iron accumulation in the brain.     

Iron and neurodegenerative disorders

The brain shares with other organs the need for a constant and readily available supply of iron and has a similar array of proteins available to it for iron transport, storage, and regulation. However, unlike other organs, the brain places demands on iron availability that are regional, cellular, and age sensitive. Failure to meet these demands for iron with an adequate supply in a timely manner can result in persistent neurological and cognitive dysfunction. Consequently, the brain has developed mechanisms to maintain a continuous supply of iron. However, in a number of common neurodegenerative disorders, there appears to be an excess accumulation of iron in the brain that suggests a loss of the homeostatic mechanisms responsible for regulating iron in the brain. These systems are reviewed in this article. As a result of a loss in iron homeostasis, the brain becomes vulnerable to iron-induced oxidative stress. Oxidative stress is a confounding variable in understanding the cell death that may result directly from a specific disease and is a contributing factor to the disease process. The underlying pathogenic event in oxidative stress is cellular iron mismanagement.     

Noise as a cause of neurodegenerative disorders: molecular and cellular mechanisms

Neurological Sciences - Noise as an environmental stressor becomes of increasing importance in our industrialized world, and especially traffic noise from the environment represents a potential...     

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.     

The role of the brain renin-angiotensin system in neurodegenerative disorders

The primary function of the renin-angiotensin system (RAS) is to maintain fluid homeostasis and regulate blood pressure. Several components of the RAS, namely angiotensinogen, angiotensin converting enzyme, angiotensin II and their receptors, are found in the CNS suggesting the possibility of a localized RAS in the brain. Cognitively disabling neurodegenerative disorders such as Alzheimer's disease or vascular dementia show vascular lesions, and the brain RAS has been suggested to contribute to the disease process. The aim of this brief review is to summarize the current state of research in this field with emphasis on RAS-related alterations during the course of neurodegenerative disorders.     

Apoptosis: a key in neurodegenerative disorders

Apoptosis is an important process in the development of the nervous system. Typically, approximately 50% of the neurons apoptose during neurogenesis before the nervous system matures. However, recent paradigms implicate premature apoptosis and/or aberrations in the fine control of neuronal apoptosis in the pathogenesis of a variety of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinal muscular atrophy, stroke, brain trauma, spinal cord injury, and diabetic neuropathy. This review will focus on the current concepts salient to understanding the apoptosis death program, the mediators and control of cellular apoptosis, and the relationship between aberrant apoptosis and genesis of neurodegenerative disorders. The discussion will also highlight current advances in methodology, such as utilization of neuronal cell lines and mutant animal models, in investigations of neuronal apoptotic death. The knowledge of apoptosis mechanisms could underpin the basis for development of novel therapeutic strategies and treatment modalities that are directed at control of the neuronal apoptotic death program.     

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.     

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 pathology: a marker of neurodegenerative disorders

Tau is not only a basic component of neurofibrillary degeneration, but is also an aetiological factor, as demonstrated by mutations on the tau gene responsible for frontotemporal dementias with parkinsonism linked to chromosome 17. Polymorphisms on the tau gene and the hierarchical invasion of neocortical areas by tau pathology in numerous sporadic neurodegenerative diseases also suggest that tau pathology is a primary pathogenic event in non-familial dementing diseases and a lead for solid diagnostic and therapeutic approaches.     

Are pathological lesions in neurodegenerative disorders the cause or the effect of the degeneration?

Pathological lesions in the form of extracellular protein deposits, intracellular inclusions and changes in cell morphology occur in the brain in the majority of neurodegenerative disorders. Studies of the presence, distribution, and molecular determinants of these lesions are often used to define individual disorders and to establish the mechanisms of lesion pathogenesis. In most disorders, however, the relationship between the appearance of a lesion and the underlying disease process is unclear. Two hypotheses are proposed which could explain this relationship: (i) lesions are the direct cause of the observed neurodegeneration (‘causal’ hypothesis); and (ii) lesions are a reaction to neurodegeneration (‘reaction’ hypothesis). These hypotheses are considered in relation to studies of the morphology and molecular determinants of lesions, the effects of gene mutations, degeneration induced by head injury, the effects of experimentally induced brain lesions, transgenic studies and the degeneration of anatomical pathways. The balance of evidence suggests that in many disorders, the appearance of the pathological lesions is a reaction to degenerative processes rather than being their cause. Such a conclusion has implications both for the classification of neurodegenerative disorders and for studies of disease pathogenesis.     

The role of neuronal growth factors in neurodegenerative disorders of the human brain

Recent evidence suggests that neurotrophic factors that promote the survival or differentiation of developing neurons may also protect mature neurons from neuronal atrophy in the degenerating human brain. Furthermore, it has been proposed that the pathogenesis of human neurodegenerative disorders may be due to an alteration in neurotrophic factor and/or trk receptor levels. The use of neurotrophic factors as therapeutic agents is a novel approach aimed at restoring and maintaining neuronal function in the central nervous system (CNS). Research is currently being undertaken to determine potential mechanisms to deliver neurotrophic factors to selectively vulnerable regions of the CNS. However, while there is widespread interest in the use of neurotrophic factors to prevent and/or reduce the neuronal cell loss and atrophy observed in neurodegenerative disorders, little research has been performed examining the expression and functional role of these factors in the normal and diseased human brain. This review will discuss recent studies and examine the role members of the nerve growth factor family (NGF, BDNF and NT-3) and trk receptors as well as additional growth factors (GDNF, TGF-α and IGF-I) may play in neurodegenerative disorders of the human brain.     

The role of the blood brain barrier in neurodegenerative disorders and their treatment

Neurodegenerative disorders represent a major medical challenge that is set to increase substantially in the decades ahead with the massive increase in the number of people in the world aged 65 or more. Neuroprotective therapeutics have the potential to play a key role in helping manage this growing global burden of long-term neurological care. However, neuropharmaceutical research is associated with significant challenges including: (1) the complexity of the brain (the cause of the majority of neurodegenerative disorders remains unknown); (2) the liability of central nervous system (CNS) drugs to cause CNS side effects (which limits their use); and (3) the requirement of neuropharmaceuticals to cross the blood-brain barrier (BBB). The BBB itself also plays a key role in most (if not all) neurodegenerative disorders since BBB dysfunction inevitably leads to inflammatory change including the movement of immune cells and immune mediators into the brain, which then contribute to the process of neurodegeneration. This review focuses on the role of the BBB in both neurodegenerative disorders and neuropharmaceutical research.     

Iron in chronic brain disorders: Imaging and neurotherapeutic implications

Iron is important for brain oxygen transport, electron transfer, neurotransmitter synthesis, and myelin production. Though iron deposition has been observed in the brain with normal aging, increased iron has also been shown in many chronic neurological disorders including Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis. In vitro studies have demonstrated that excessive iron can lead to free radical production, which can promote neurotoxicity. However, the link between observed iron deposition and pathological processes underlying various diseases of the brain is not well understood. It is not known whether excessive in vivo iron directly contributes to tissue damage or is solely an epiphenomenon. In this article, we focus on the imaging of brain iron and the underlying physiology and metabolism relating to iron deposition. We conclude with a discussion of the potential implications of iron-related toxicity to neurotherapeutic development.     

Molecular mechanisms of brain aging and neurodegenerative disorders: lessons from dietary restriction

The application of modern molecular and cell biology technologies to studies of the neurobiology of aging provides a window on the molecular substrates of successful brain aging and neurodegenerative disorders. Aging is associated with increased oxidative stress, disturbances in energy metabolism and inflammation-like processes. Dietary restriction (DR) can extend lifespan and might increase the resistance of the nervous system to age-related neurodegenerative disorders. The neuroprotective effect of DR involves a preconditioning response in which the production of neurotrophic factors and protein chaperones is increased resulting in protection against oxyradical production, stabilization of cellular calcium homeostasis, and inhibition of apoptosis. DR might also enhance neurogenesis, synaptic plasticity and self-repair mechanisms.     

Sleep in neurodegenerative disorders

Neurodegenerative disorders are a group of heterogeneous, progressive disorders of varying etiology that affect one or more systems. They occur predominantly at older age, during which the structure and amount of sleep undergo changes. Neurodegenerative processes cause structural changes of the sleep/wake generators in the brainstem which result in disorders such as daytime sleepiness, insomnia, sleep-related movement and breathing disturbances, and disorders of the circadian rhythms. Some sleep disorders manifest years before the onset of neurodegenerative disorders and may serve as predictors. Polysomnography shows sleep fragmentation, tonic or phasic movements of the extremities, alteration of respiratory muscles, reduced slow wave sleep, REM sleep absence or without muscle atonia, increased arousal or wake activity, epileptiform EEG activity, and changes in sleep-related breathing. Very frequently, REM sleep behaviour disorder is associated with neurodegenerative disorders. In this overview we present symptoms, pathophysiology, and polysomnographic findings of sleep disorders in prevalent neurodegenerative disorders.