Detection of Protein Aggregates in Brain and Cerebrospinal Fluid Derived from Multiple Sclerosis Patients

David, Monique; Tayebi, Mourad

doi:10.3389/fneur.2014.00251

Cited by 43 publications

(33 citation statements)

References 19 publications

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“…These markers also appear more frequently in acute or hypoxic rather than progressive or normoxic lesions, respectively, suggesting more aggressive and/or less oxygenated brain tissue is affected with rapid, deleterious results. Interestingly, they found significant increases in expression of APP in active lesions relative to normal-appearing white matter later confirmed in a 2014 study (Haider et al, 2011, David and Tayebi, 2014). Whether this change in APP has any direct relation to the development of MS remains unclear.…”

Section: Introductionmentioning

confidence: 65%

Oxidative and nitrative stress in neurodegeneration

Cobb

Cole

2015

Neurobiology of Disease

241

180

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Aerobes require oxygen for metabolism and normal free radical formation. As a result, maintaining the redox homeostasis is essential for brain cell survival due to their high metabolic energy requirement to sustain electrochemical gradients, neurotransmitter release, and membrane lipid stability. Further, brain antioxidant levels are limited compared to other organs and less able to compensate for reactive oxygen and nitrogen species (ROS/RNS) generation which contribute oxidative/nitrative stress (OS/NS). Antioxidant treatments such as vitamin E, minocycline, and resveratrol mediate neuroprotection by prolonging the incidence of or reversing OS and NS conditions. Redox imbalance occurs when the antioxidant capacity is overwhelmed, consequently leading to activation of alternate pathways that remain quiescent under normal conditions. If OS/NS fails to lead to adaptation, tissue damage and injury ensue, resulting in cell death and/or disease. The progression of OS/NS-mediated neurodegeneration along with contributions from microglial activation, dopamine metabolism, and diabetes comprise a detailed interconnected pathway. This review proposes a significant role for OS/NS and more specifically, lipid peroxidation (LPO) and other lipid modifications, by triggering microglial activation to elicit a neuroinflammatory state potentiated by diabetes or abnormal dopamine metabolism. Subsequently, sustained stress in the neuroinflammatory state overwhelms cellular defenses and prompts neurotoxicity resulting in the onset or amplification of brain damage.

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Section: Introductionmentioning

confidence: 65%

Oxidative and nitrative stress in neurodegeneration

Cobb

Cole

2015

Neurobiology of Disease

241

180

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“…In more chronic lesions, the levels of APP immunoreactivity were generally lower than in acute lesions, which were mainly found on reactive astrocytes, their processes and a few macrophages/microglia, depending on the stage of plaque development. The presence of soluble oligomers, normally associated with protein-misfolding diseases, in the brain and cerebrospinal fluid of MS patients as published recently gives us robust evidence of amyloid activity in MS [8]. The detection of these soluble oligomers can also play an important diagnostic role in MS.…”

Section: Role Of Amyloid In Msmentioning

confidence: 99%

Role of Amyloid from a Multiple Sclerosis Perspective: A Literature Review

Chandra¹

2015

Neuroimmunomodulation

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The traditional concept of multiple sclerosis (MS), that it is primarily a white matter inflammatory disease, has changed a great deal. Thanks to the recent development witnessed in MS research, a whole new idea has emerged that MS is a neurodegenerative disease, and neurodegeneration occurs rather earlier in the pathological process. This has also led to the foundation of the hypothesis that two fundamentally different diseases, Alzheimer's disease (AD) and MS, may share a common mechanism of neurodegeneration. Conventionally, amyloid is thought to be a consequence of protein misfolding and aggregation and is most notorious for its association with debilitating and chronic human diseases. Amyloid is implicated to be related with the deterioration and progression of AD. The finding of amyloid precursor protein expression in axons around the plaque in MS, as well as the correlation of amyloid-β (Aβ) with different stages of MS, has clearly indicated that amyloid plays some kind of key role in MS disease pathogenesis. Excitingly, a paradoxical phenomenon of Aβ has also been observed in several studies recently. It has been shown that amyloid might actually be helping in ameliorating the inflammatory effect in diseases like AD and MS. Amyloid imaging allows earlier diagnosis of MS by taking advantage of the relation of amyloid with MS. This will have a big impact on patient diagnosis and management. In this review I have included the findings of research studies dating from several years back to the most recent ones. Through this review I have tried to show the critical role of amyloid in MS and the importance of investigating through PET imaging.

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“…Soluble oligomers have been detected in the brain and cerebral spinal fl uid of MS patients [19] . Meanwhile, oxidized protein aggregates increase in EAE, probably due to the reduced autophagy level [20] .…”

Section: Introductionmentioning

confidence: 99%

Role of autophagy in the pathogenesis of multiple sclerosis

Liang

2015

Neurosci. Bull.

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Autophagy plays an important role in maintaining the cellular homeostasis. One of its functions is to degrade unnecessary organelles and proteins for energy recycling or amino-acids for cell survival. Ablation of autophagy leads to neurodegeneration. Multiple sclerosis (MS), a permanent neurological impairment typical of chronic inflammatory demyelinating disorder, is an auto-immune disease of the central nervous system (CNS). Autophagy is tightly linked to the innate and adaptive immune systems during the autoimmune process, and several studies have shown that autophagy directly participates in the progress of MS or experimental autoimmune encephalomyelitis (EAE, a mouse model of MS). Dysfunction of mitochondria that intensively infl uences the autophagy pathway is one of the important factors in the pathogenesis of MS. Autophagy-related gene (ATG) 5 and immune-related GTPase M (IRGM) 1 are increased, while ATG16L2 is decreased, in T-cells in EAE and active relapsing-remitting MS brains. Administration of rapamycin, an inhibitor of mammalian target of rapamycin ( mTOR), ameliorates relapsing-remitting EAE. Infl ammation and oxidative stress are increased in MS lesions and EAE, but Lamp2 and the LC3-II/LC3-I ratio are decreased. Furthermore, autophagy in various glial cells plays important roles in regulating neuro-infl ammation in the CNS, implying potential roles in MS. In this review, we discuss the role of autophagy in the peripheral immune system and the CNS in neuroinfl ammation associated with the pathogenesis of MS. Keywords: autophagy; multiple sclerosis; neuro-infl ammation ·Review· IntroductionAutophagy, a lysosome-dependent degradation pathway, contributes to maintaining cellular homeostasis. Clearance of long-lived proteins, unnecessary organelles, and aggregate-prone proteins is mainly executed by autophagy for recycling cellular materials [1] . There are three subtypes of autophagy, macroautophagy, chaperone-mediated autophagy (CMA), and mitophagy. Macroautophagy is the major type for selective degradation of protein aggregates or misfolded proteins. The ubiquitin-labeled proteins are recognized by autophagy receptors, such as p62, neighbor of BRCA1 gene 1 (NBR1), and NIP3-like protein X (NIX), to form autophagosomes that then fuse with lysosomes for degradation. Many autophagy-related genes function during this process, such as Unc51-like kinase (ULK1) and autophagy-related gene (ATG) 5. Mammalian target of rapamycin (mTOR) represses autophagy by regulating ULK1 phosphorylation, while AMPK activates this process.CMA mediates the degradation of large molecular-weight proteins containing the KFERQ motif recognized by heat shock cognate protein of 70 kDa (HSC70). The substrate is then escorted to lysosome-associated membrane protein 2 (LAMP2A) for lysosomal degradation. Mitophagy is responsible for the degradation of damaged mitochondria.Parkin and PINK1 play critical roles in this process [2] . More Neurosci Bull August 1, 2015, 31(4): 435-444 436 attention has been paid to autophagy in the path...

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Detection of Protein Aggregates in Brain and Cerebrospinal Fluid Derived from Multiple Sclerosis Patients

Cited by 43 publications

References 19 publications

Oxidative and nitrative stress in neurodegeneration

Oxidative and nitrative stress in neurodegeneration

Role of Amyloid from a Multiple Sclerosis Perspective: A Literature Review

Role of autophagy in the pathogenesis of multiple sclerosis

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