The Deleterious Effects of Oxidative and Nitrosative Stress on Palmitoylation, Membrane Lipid Rafts and Lipid-Based Cellular Signalling: New Drug Targets in Neuroimmune Disorders

Morris, Gerwyn; Walder, Ken; Puri, Basant K.; Berk, Michael; Maes, Michaël

doi:10.1007/s12035-015-9392-y

Cited by 52 publications

(34 citation statements)

References 304 publications

(308 reference statements)

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“…3) [172–174]. Alteration of structure and fluidity of plasma membrane associated with lipid peroxidation could affect the organization and function of dendritic spines, signaling pathways, receptor trafficking, and localization [175]. Indeed, alterations in lipid trafficking and metabolism affect membrane fluidity and lipid homeostasis early in ApoE4 carriers [92, 137, 176, 177].…”

Section: Oxidative Stress and Synaptic Dysfunction In Alzheimer’s Dismentioning

confidence: 99%

Oxidative Stress, Synaptic Dysfunction, and Alzheimer’s Disease

Tönnies

Trushina

2017

JAD

1,273

791

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Alzheimer’s disease (AD) is a devastating neurodegenerative disorder without a cure. Most AD cases are sporadic where age represents the greatest risk factor. Lack of understanding of the disease mechanism hinders the development of efficacious therapeutic approaches. The loss of synapses in the affected brain regions correlates best with cognitive impairment in AD patients and has been considered as the early mechanism that precedes neuronal loss. Oxidative stress has been recognized as a contributing factor in aging and in the progression of multiple neurodegenerative diseases including AD. Increased production of reactive oxygen species (ROS) associated with age- and disease-dependent loss of mitochondrial function, altered metal homeostasis, and reduced antioxidant defense directly affect synaptic activity and neurotransmission in neurons leading to cognitive dysfunction. In addition, molecular targets affected by ROS include nuclear and mitochondrial DNA, lipids, proteins, calcium homeostasis, mitochondrial dynamics and function, cellular architecture, receptor trafficking and endocytosis, and energy homeostasis. Abnormal cellular metabolism in turn could affect the production and accumulation of amyloid-β (Aβ) and hyperphosphorylated Tau protein, which independently could exacerbate mitochondrial dysfunction and ROS production, thereby contributing to a vicious cycle. While mounting evidence implicates ROS in the AD etiology, clinical trials with antioxidant therapies have not produced consistent results. In this review, we will discuss the role of oxidative stress in synaptic dysfunction in AD, innovative therapeutic strategies evolved based on a better understanding of the complexity of molecular mechanisms of AD, and the dual role ROS play in health and disease.

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Section: Oxidative Stress and Synaptic Dysfunction In Alzheimer’s Dismentioning

confidence: 99%

Oxidative Stress, Synaptic Dysfunction, and Alzheimer’s Disease

Tönnies

Trushina

2017

JAD

1,273

791

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“…However, from the perspective of this article, it should be emphasized that the activity of NKA is not just dependent on adequate supplies of ATP but is heavily influenced by the redox state of the intracellular and extracellular environment. Unsurprisingly, animal and human studies confirm that oxidative and nitrosative stress inhibits NKA activity in rat hippocampus and prefrontal cortex [253,254] and in patients with SZ and BPD [255,256]. A combination of oxidative stress would also appear to explain the downregulation of NKA activity seen in MDD, AD, and other neurodegenerative diseases (reviewed by [257]).…”

Section: Nutritional Ketosis Astrogliosis and Nka Functionmentioning

confidence: 97%

“…Briefly, several authors have also reported strong negative correlations between the extent of membrane lipid peroxidation and NKA activity in vivo in illnesses as diverse as cardiovascular disease, SZ, and BPD [255,256,261]. The relationship between increased membrane lipid peroxidation and increasing NKA dysfunction appears to be mediated by decreased membrane fluidity and PUFA content [260,262].…”

Section: Nutritional Ketosis Astrogliosis and Nka Functionmentioning

confidence: 97%

Nutritional ketosis as an intervention to relieve astrogliosis: Possible therapeutic applications in the treatment of neurodegenerative and neuroprogressive disorders

et al. 2020

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Nutritional ketosis, induced via either the classical ketogenic diet or the use of emulsified medium-chain triglycerides, is an established treatment for pharmaceutical resistant epilepsy in children and more recently in adults. In addition, the use of oral ketogenic compounds, fractionated coconut oil, very low carbohydrate intake, or ketone monoester supplementation has been reported to be potentially helpful in mild cognitive impairment, Parkinson’s disease, schizophrenia, bipolar disorder, and autistic spectrum disorder. In these and other neurodegenerative and neuroprogressive disorders, there are detrimental effects of oxidative stress, mitochondrial dysfunction, and neuroinflammation on neuronal function. However, they also adversely impact on neurone–glia interactions, disrupting the role of microglia and astrocytes in central nervous system (CNS) homeostasis. Astrocytes are the main site of CNS fatty acid oxidation; the resulting ketone bodies constitute an important source of oxidative fuel for neurones in an environment of glucose restriction. Importantly, the lactate shuttle between astrocytes and neurones is dependent on glycogenolysis and glycolysis, resulting from the fact that the astrocytic filopodia responsible for lactate release are too narrow to accommodate mitochondria. The entry into the CNS of ketone bodies and fatty acids, as a result of nutritional ketosis, has effects on the astrocytic glutamate–glutamine cycle, glutamate synthase activity, and on the function of vesicular glutamate transporters, EAAT, Na+, K+-ATPase, Kir4.1, aquaporin-4, Cx34 and KATP channels, as well as on astrogliosis. These mechanisms are detailed and it is suggested that they would tend to mitigate the changes seen in many neurodegenerative and neuroprogressive disorders. Hence, it is hypothesized that nutritional ketosis may have therapeutic applications in such disorders.

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“…Mechanisms underpinning the detrimental effects of excessive ROS levels on synaptic function are underpinned by oxidation of cytosolic and membrane proteins and peroxidation of membrane lipids [243,244]. For example, several research teams have reported that lipid peroxidation in presynaptic membranes impedes fusion pore opening, thereby restricting SV exocytosis, resulting in the abnormal retention of SVs within presynaptic active zones [245,246].…”

Section: Oxidative Stress and The Development Of Synaptic Dysfunctionmentioning

confidence: 99%

Could Alzheimer’s Disease Originate in the Periphery and If So How So?

et al. 2018

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The classical amyloid cascade model for Alzheimer's disease (AD) has been challenged by several findings. Here, an alternative molecular neurobiological model is proposed. It is shown that the presence of the APOE ε4 allele, altered miRNA expression and epigenetic dysregulation in the promoter region and exon 1 of TREM2, as well as ANK1 hypermethylation and altered levels of histone post-translational methylation leading to increased transcription of TNFA, could variously explain increased levels of peripheral and central inflammation found in AD. In particular, as a result of increased activity of triggering receptor expressed on myeloid cells 2 (TREM-2), the presence of the apolipoprotein E4 (ApoE4) isoform, and changes in ANK1 expression, with subsequent changes in miR-486 leading to altered levels of protein kinase B (Akt), mechanistic (previously mammalian) target of rapamycin (mTOR) and signal transducer and activator of transcription 3 (STAT3), all of which play major roles in microglial activation, proliferation and survival, there is activation of microglia, leading to the subsequent (further) production of cytokines, chemokines, nitric oxide, prostaglandins, reactive oxygen species, inducible nitric oxide synthase and cyclooxygenase-2, and other mediators of inflammation and neurotoxicity. These changes are associated with the development of amyloid and tau pathology, mitochondrial dysfunction (including impaired activity of the electron transport chain, depleted basal mitochondrial potential and oxidative damage to key tricarboxylic acid enzymes), synaptic dysfunction, altered glycogen synthase kinase-3 (GSK-3) activity, mTOR activation, impairment of autophagy, compromised ubiquitin-proteasome system, iron dyshomeostasis, changes in APP translation, amyloid plaque formation, tau hyperphosphorylation and neurofibrillary tangle formation.

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The Deleterious Effects of Oxidative and Nitrosative Stress on Palmitoylation, Membrane Lipid Rafts and Lipid-Based Cellular Signalling: New Drug Targets in Neuroimmune Disorders

Cited by 52 publications

References 304 publications

Oxidative Stress, Synaptic Dysfunction, and Alzheimer’s Disease

Oxidative Stress, Synaptic Dysfunction, and Alzheimer’s Disease

Nutritional ketosis as an intervention to relieve astrogliosis: Possible therapeutic applications in the treatment of neurodegenerative and neuroprogressive disorders

Could Alzheimer’s Disease Originate in the Periphery and If So How So?

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