Sphingolipids in Neurodegeneration

Although the brain contains a high content of sphingolipids, we know relatively little about the roles that sphingolipids play in regulating neural functions. Once regarded only for their structural roles in maintaining the integrity of cellular and sub-cellular compartments, it is now apparent that many sphingolipid species are biologically active and play important roles in regulating signaling events. Recent technological and scientific advances are rapidly increasing our knowledge of the roles that sphingolipids play in regulating normal neural activity. Likewise, we are beginning to understand how perturbations in sphingolipid metabolism contribute to the pathogenesis of a variety of neurodegenerative conditions. In this special issue of NeuroMolecular Medicine, we present a series of review articles that summarize new and emerging technologies for the analysis of sphingolipids, sphingolipid metabolic pathways, and how dysfunctions in sphingolipid metabolism contribute to neurodegeneration in lysosomal storage disorders, Alzheimer’s disease and Multiple Sclerosis.     

Modeling Neurodegeneration in Zebrafish

The zebrafish, Danio rerio, has been established as an excellent vertebrate model for the study of developmental biology and gene function. It also has proven to be a valuable model to study human diseases. Here, we reviewed recent publications using zebrafish to study the pathology of human neurodegenerative diseases including Parkinson’s, Huntington’s, and Alzheimer’s. These studies indicate that zebrafish genes and their human homologues have conserved functions with respect to the etiology of neurodegenerative diseases. The characteristics of the zebrafish and the experimental approaches to which it is amenable make this species a useful complement to other animal models for the study of pathologic mechanisms of neurodegenerative diseases and for the screening of compounds with therapeutic potential.     

Neurodegeneration in Alzheimer disease

Alzheimer disease (AD), the most common dementia of the elderly, results from a significant loss of neuronal cells in brain regions important in memory and cognition. Several lines of evidence suggest that the Aβ peptide is directly responsible for some of this neuronal cell death. We review recent evidence from in vitro toxicity and immunohistochemical studies that suggest some of the cell loss in AD is the result of apoptosis.     

Neurodegeneration in Alzheimer disease

Alzheimer disease (AD), the most common dementia of the elderly, results from a significant loss of neuronal cells in brain regions important in memory and cognition. Several lines of evidence suggest that the Aβ peptide is directly responsible for some of this neuronal cell death. We review recent evidence from in vitro toxicity and immunohistochemical studies that suggest some of the cell loss in AD is the result of apoptosis.     

Neurodegeneration and plasticity

Neurofibrillary degeneration, associated with the formation of paired helical filaments (PHF), is one of the critical neuropathological hallmarks of Alzheimer's disease (AD). Although the microtubule-associated protein tau in a hyperphosphorylated form has been established as primary PHF constituent, the process of tau phosphorylation and its potential link to degeneration is not very well understood, mostly because of the lack of a physiological in vivo model of PHF-like tau phosphorylation. PHF formation in AD follows a hierarchical pattern of development throughout different cortical areas, which closely matches the pattern of neuronal plasticity in the adult brain. Those brain areas are most early and most severely affected which are involved in the regulation of memory, learning, perception, self-awareness, consciousness, and higher brain functions that require a life-long re-fitting of connectivity, a process based on a particularly high degree of plasticity. Failures of synaptic plasticity are, thus, assumed to represent early events in the course of AD that eventually lead to alteration of tau phosphorylation. Recently, we have used the hibernation cycle, a physiological model of adaptation associated with an extraordinary high degree of structural neuronal plasticity, to analyze the potential link between synaptic plasticity, synaptic detachment and the regulation of tau phosphorylation. During torpor, a natural state of hypothermia, synaptic contacts between mossy fibers and hippocampal pyramidal neurons undergo dramatic regressive changes that are fully reversible very rapidly during euthermy. This rapid, reversible, and repeated regression of synaptic and dendritic components on CA3 neurons is associated with a reversible PHF-like phosphorylation of tau at a similar time course. The repeated formation and degradation of PHF-tau might, thus, represent a physiological mechanism not necessarily associated with pathological effects. These findings implicate an essential link between neuronal plasticity and PHF-like phosphorylation of tau, potentially involved in neurofibrillary degeneration.     

Electrophilic Cyclopentenone Isoprostanes in Neurodegeneration

Although oxidative stress has been implicated in the pathogenesis of numerous neurodegenerative conditions, the precise mechanisms by which reactive oxygen species (ROS) induce neuronal death are still being explored. The generation of reactive lipid peroxidation products is thought to contribute to ROS neurotoxicity. Isoprostanes (IsoPs), prostaglandin-like molecules formed in vivo via the ROS-mediated oxidation of arachidonic acid, have been previously demonstrated to be formed in increased amounts in the brains of patients with various neurodegenerative diseases. Recently, we have identified a new class of IsoPs, known as A(2)- and J(2)-IsoPs or cyclopentenone IsoPs, which are highly reactive electrophiles and form adducts with thiol-containing molecules, including cysteine residues in proteins and glutathione. Cyclopentenone IsoPs are favored products of the IsoP pathway in the brain and are formed abundantly after oxidant injury. These compounds also potently induce neuronal apoptosis by a mechanism which involves glutathione depletion, ROS generation, and activation of several redox-sensitive pathways that overlap with those involved in other forms of oxidative neurodegeneration. Cyclopentenone IsoPs also enhance neurodegeneration caused by other insults at biologically relevant concentrations. These data are reviewed, whereas new data demonstrating the neurotoxicity of J-ring IsoPs and a discussion of the possible role of cyclopentenone IsoPs as contributors to neurodegeneration are presented.     

Future Directions in Imaging Neurodegeneration

Neuroimaging comprises a powerful set of instruments to diagnose various neurodegenerative disorders, clarifies their neurobiology, and monitors their treatment. Magnetic resonance imaging depicts volume changes, as well as abnormalities in functional and structural connectivity. Positron emission tomography (PET) allows for the quantification of regional cerebral metabolism, characteristically altered in Alzheimer’s disease, amyotrophic lateral sclerosis, diffuse Lewy-body disease, and the frontotemporal dementias. PET is also used to measure several neurotransmitters, such as dopamine, which is abnormal in Parkinson’s disease, and to determine the abnormal brain deposition of amyloid-β and tau, as well as brain inflammation. These instruments allow for the quantification in vivo and the longitudinal follow-up of key neurobiological events in neurodegeneration. For instance, amyloid imaging is being used not only to determine who has excess amyloid in the brain but also to investigate whether removing it may slow the deposition of tau and delay cognitive impairment in Alzheimer’s disease.     

Neurodegeneration in autoimmune CNS inflammation

Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system, in which the myelin sheath has been considered to be the primary target for many years. However, an increasing number of reports have focused on neurodegenerative aspects of the disease pathogenesis. Recent studies in post-mortem MS biopsies and in the animal model Experimental Autoimmune Encephalomyelitis (EAE) have shown that key features of neurodegeneration, i.e. axonal transection, neuronal cell atrophy and neuronal death already occur in early disease phases. Furthermore, it has become clear that irreversible disability correlates stronger with the neuronal affectation than with demyelination. However the cause of neuronal damage still remains elusive, since both demyelination-dependent and direct immune cell-mediated mechanisms have been suggested so far. Here, we summarize the current concepts and recently identified molecular mechanisms of inflammatory neurodegeneration in autoimmune CNS inflammation and highlight the role of different immune cells in the complex network of interactions leading to neuronal damage.     

Neurodegeneration in branch retinal vein occlusion

正One of the most common forms of visual impairment and reduction in overall visual acuity is branch retinal vein occlusion(BRVO),second only to diabetic retinopathy(Rogers et al.,2010;Sun et al.,2013).Unlike central retinal vein occlusion(CRVO)which is a similar macular disease,BRVO is extremely more prevalent and generally only affects a smaller portion of the retina(Osborne et al.,2004)due to the nature of the disease.While initially the impairment can be extreme,evidence     

Neurodegeneration and inflammation in Parkinson's disease

Parkinson's disease (PD) is characterized by the progressive degeneration of dopamine (DA) neurons of the substantia nigra pars compacta (SNpc) accompanied by a buildup of proteinaceous aggregates termed Lewy bodies (LB). In addition to protein aggregation and the loss of DA signaling, PD is also characterized by an active immune response. T-cell infiltration accompanies activated microglial and astrocytic accumulation in and around the SNpc. Although potentially beneficial, microglial activation is most likely responsible for furthering disease pathology and DA neuron degeneration through the release of harmful substances such as pro-inflammatory cytokines, reactive oxidative species and reactive nitrogen species. Activation of the NF-κB death pathway has been shown to occur following microglial activation related release of Cox-2, IL-1β, and Toll-like receptor activation, resulting in increased degeneration of DA neurons of the SNpc. Blockade of microglial activation can lead to DA neuron protection in animal models of PD; however, clinical application of anti-inflammatory drugs has not yielded similar benefits. Future therapeutic designs must take into account the multifactorial nature of PD, including the varied roles of the adaptive and innate immune responses.     

Neurodegeneration and neuroprotection in Parkinson disease

Many of the motoric features that define Parkinson disease (PD) result primarily from the loss of the neuromelanin (NM)-containing dopamine (DA) neurons of the substantia nigra (SN), and to a lesser extent, other mostly catecholaminergic neurons, and are associated with cytoplasmic “Lewy body” inclusions in some of the surviving neurons. While there are uncommon instances of familial PD, and rare instances of known genetic causes, the etiology of the vast majority of PD cases remains unknown (i.e., idiopathic). Here we outline genetic and environmental findings related to PD epidemiology, suggestions that aberrant protein degradation may play a role in disease pathogenesis, and pathogenetic mechanisms including oxidative stress due to DA oxidation that could underlie the selectivity of neurodegeneration. We then outline potential approaches to neuroprotection for PD that are derived from current notions on disease pathogenesis.     

Neurodegeneration and neuroprotective agents in multiple sclerosis

Multiple sclerosis (MS) is an autoimmune/ inflammatory disease of the central nervous system (CNS). MS affects more than two million people worldwide and has been recognized as the leading cause of neurological disability in young adults. MS has long been considered as a CNS disease of demyelination and inflammation. Axonal degeneration has however been increasingly accepted as a key pathogenetic element. Certain noninvasive tests such as optic coherence tomography (OCT), magnetization transfer imaging (MTI), and proton magnetic resonance spectroscopy (MRS) might be superior in early detection of axonal loss and neurodegeneration as compared to conventional neuroimaging studies. New therapeutic strategies targeting the neurodegenerative process in MS provide hope to the MS community. A number of phase II or III clinical trials that are designed to target such specific pathogenetic mechanisms include sodium channel blockers, matrix metalloproteinases (MMP) inhibitors, c-AMP selective phosphodiesterase inhibitors, NMDA receptor antagonists, amongst others. In the current review, we will discuss the current understanding of the mechanisms of neurodegeneration in MS, agents with neuroprotective properties, patents currently available and, their possible application in the treatment of MS.     

Brain Accumulation of Amyloid-beta in Non-Alzheimer Neurodegeneration

We report an unusual case of amyotrophic lateral sclerosis (ALS) marked by extensive cerebral amyloid-beta deposition in small and medium-size vessels, capillaries, and perivascular plaques in the cerebral cortex, and in most leptomeningeal vessels. Despite considerable cerebral amyloidosis, the patient remained cognitively intact until death. For comparison with other neuro-degenerative diseases and normal aging, we assessed the densities of amyloid-beta-immunoreactive cortical vessels and plaques in matched frontal and temporal lobe sections from archival uncomplicated cases of Alzheimer's disease (N=10), Pick's disease (PkD; N=4), Parkinson's disease (PD; N=6), Diffuse Lewy body disease (DLBD; N=7), progressive supranuclear palsy (PSP; N=5), multiple systems atrophy (MSA; N=4), ALS (N=7), or normal aging (N=10) by semi-quantitative grading (0 to 3+). Moderate (2+) or abundant (3+) cerebrovascular amyloid-beta immunoreactivity was detected in 8/10 AD, 3/7 DLBD, 3/6 PD, 1 each with PSP or PkD, and 2/10 controls. Moderate or abundant densities of amyloid-beta-immunoreactive diffuse plaques were detected in all cases of AD or DLBD, 4/6 with PD, 3/5 with PSP, and 2/10 controls. Moderate or abundant amyloid-beta-immunoreactive mature (dense core) plaques were present in all cases of AD or DLBD, and 3 each with PD or PSP. Importantly, amyloid-beta-immunoreactivity was not observed in the 4 MSA or 7 archival ALS cases. This study demonstrates that prominent amyloid-beta accumulation in cerebral vessels and plaques occurs frequently in AD, DLBD, PSP, and PD, but not in ALS or MSA, indicating that the case described is unique. The lack of cognitive impairment in the case presented argues against the idea that extensive amyloid-beta deposition in the brain causes dementia.     

Neurodegeneration and -protection in autoimmune CNS inflammation

Neurodegeneration in multiple sclerosis (MS) is the structural correlate of permanent neurological disability in patients. The histopathological features of neurodegeneration include destruction of axons as well as apoptotic cell death of neuronal cell bodies. Therapeutic efforts to control these clinically important aspects of MS pathology showed limited success so far. In this review article, we give an overview about the current knowledge concerning the molecular mechanisms of neurodegeneration in autoimmune inflammation that is mainly derived from animal models. Further, we critically discuss experimental neuroprotective strategies with respect to their functional relevance and differentiate between anti-apoptotic and axon protective treatment approaches.     

Neurodegeneration with brain iron accumulation

Neurodegeneration with brain iron accumulation (NBIA) describes a group of progressive extrapyramidal disorders with radiographic evidence of focal iron accumulation in the brain, usually in the basal ganglia. Patients previously diagnosed with Hallervorden-Spatz syndrome fall into this category. Mutations in the PANK2 gene account for the majority of NBIA cases and cause an autosomal recessive inborn error of coenzyme A metabolism called pantothenate kinase-associated neurodegeneration (PKAN). PKAN is characterized by dystonia and pigmentary retinopathy in children or speech and neuropsychiatric disorders in adults. In addition, a specific pattern on brain MRI, called the eye-of-the-tiger sign, is virtually pathognomonic for the disease. Pantothenate kinase is essential to coenzyme A biosynthesis, and the PANK2 protein is targeted to the mitochondria. Hypotheses of PKAN pathogenesis are based on the predictions of tissue-specific coenzyme A deficiency and the accumulation of cysteine-containing substrates. Identification of the major NBIA gene has led to more accurate clinical delineation of the diseases that comprise this group, a molecular diagnostic test for PKAN, and hypotheses for treatment.