Altered oxidant-mediated intraneuronal zinc mobilization in a triple transgenic mouse model of Alzheimer’s disease

Sensi, Stefano L.; Rapposelli, Ilario Giovanni; Frazzini, Valério; Mascetra, Nicola

doi:10.1016/j.exger.2007.10.018

Cited by 44 publications

(34 citation statements)

References 42 publications

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“…In AD transgenic animals, amyloid plaque formation is fostered by release of pre-synaptic Zn 2+ (Lee et al, 2002). The ROS-mediated mobilization of intracellular Zn 2+ from the relative binding proteins is another important piece of evidence of the role that Zn 2+ plays in the intraneuronal aggregation of Ab (Sensi et al, 2008). For these reasons, the action of metal chelators could have important effects in preventing or reducing the protein aggregation in neurodegenerative disorders (Cherny et al, 2001).…”

Section: Effects On the Metal Dyshomeostasismentioning

confidence: 98%

Neuroprotective features of carnosine in oxidative driven diseases

Bellia

Vecchio

Cuzzocrea

et al. 2011

Molecular Aspects of Medicine

111

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Section: Effects On the Metal Dyshomeostasismentioning

confidence: 98%

Neuroprotective features of carnosine in oxidative driven diseases

Bellia

Vecchio

Cuzzocrea

et al. 2011

Molecular Aspects of Medicine

111

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“…Evidence from triple-transgenic mice demonstrated that APP, PS1, and PS2 mutations produce ROS to mobilize zinc from extracellular metallothionein [79] , which may be involved in Aβ accumulation [80] .…”

Section: Metal Accumulationmentioning

confidence: 99%

Oxidative stress in Alzheimer’s disease

2014

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Oxidative stress plays a significant role in the pathogenesis of Alzheimer's disease (AD), a devastating disease of the elderly. The brain is more vulnerable than other organs to oxidative stress, and most of the components of neurons (lipids, proteins, and nucleic acids) can be oxidized in AD due to mitochondrial dysfunction, increased metal levels, infl ammation, and β-amyloid (Aβ) peptides. Oxidative stress participates in the development of AD by promoting Aβ deposition, tau hyperphosphorylation, and the subsequent loss of synapses and neurons. The relationship between oxidative stress and AD suggests that oxidative stress is an essential part of the pathological process, and antioxidants may be useful for AD treatment.Keywords: Alzheimer's disease; oxidative stress; β-amyloid; tau; metals; antioxidants ·Review· IntroductionThe human brain, although it constitutes only 2% of the body weight, consumes ~20% of the oxygen supplied by the respiratory system [1] . The high energy-consumption of the brain means that it is more susceptible to oxidative stress than any other organ. As the basic functional unit of the brain, the neuron is particularly vulnerable to oxidative damage because it has a higher metabolic rate than other cells [2] . The oxidation of lipids, proteins, and nucleic acids in neurons is a common pathological feature of Alzheimer's disease (AD) [3] . Neurons contain a large amount of polyunsaturated fatty acids (PUFAs) that can interact with reactive oxygen species (ROS), leading to a selfpropagating cascade of lipid peroxidation and molecular destruction [4] . Furthermore, neurons contain low levels of glutathione, an essential antioxidant for eliminating free radicals [5] . Therefore, neurons are highly susceptible to oxidative stress.An increased oxidative burden has been reported in the brains of non-demented elderly and/or sporadic AD patients [6,7] . Increased levels of oxidative stress biomarkers in the blood reflect such stress in the brain [8,9] . Currently, many blood markers of oxidative stress have been identified in AD patients or related animal models, including protein carbonyls and 3-nitrotyrosine [10,11] , , malondialdehyde (MDA) [12] , 4-hydroxynonenal (4-HNE), and F2-isoprostanes (F2-IsoPs) [13][14][15][16] . Apart from the intracellular accumulation of free radicals, changes in the activities or expressions of antioxidant enzymes, such as superoxide dismutase (SOD) and catalase, have also been described in both the central nervous system and peripheral tissues of AD patients [14,17] . Thus, oxidative stress is an important pathological feature in AD.However, how and where the oxidative stress originates in AD are open questions. Research has suggested that mitochondrial dysfunction [12,18,19] , metal accumulation [12,20,21] , hyperphosphorylated tau [22,23] , inflammation [24,25] , and β-amyloid (Aβ) accumulation [12,19] are the basic mechanisms underlying the induction of oxidative stress. Deficiency or destruction of components of the antioxidant system such as SOD in the mi...

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“…Toward this end we used the 3xTg-AD transgenic mouse which provides one of the most comprehensive mice models of AD by harboring PS1(M146V), APP Swe , and tau P301L transgenes (Oddo et al, 2003). Moreover, oxidative stress is extensive in the brain of the 3xTg-AD mouse (Smith et al, 2005;Sensi et al, 2008;Yao et al, 2009;Chou et al, 2011;McManus et al, 2011). The Western blot in Figure 5A, shows KCNB1 protein levels in brains of 2-, 11-, and 22-monthold animals blotted under reducing conditions (20 mM DTT).…”

Section: Kcnb1 Oxidation Is Exacerbated In Mouse Model Of Ad Brainmentioning

confidence: 99%

Toxic Role of K⁺Channel Oxidation in Mammalian Brain

Cotella¹,

Hernandez-Enriquez²,

Wu³

et al. 2012

J. Neurosci.

103

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Potassium (K ϩ ) channels are essential to neuronal signaling and survival. Here we show that these proteins are targets of reactive oxygen species in mammalian brain and that their oxidation contributes to neuropathy. Thus, the KCNB1 (Kv2.1) channel, which is abundantly expressed in cortex and hippocampus, formed oligomers upon exposure to oxidizing agents. These oligomers were ϳ10-fold more abundant in the brain of old than young mice. Oxidant-induced oligomerization of wild-type KCNB1 enhanced apoptosis in neuronal cells subject to oxidative insults. Consequently, a KCNB1 variant resistant to oxidation, obtained by mutating a conserved cysteine to alanine, (C73A), was neuroprotective. The fact that oxidation of KCNB1 is toxic, argues that this mechanism may contribute to neuropathy in conditions characterized by high levels of oxidative stress, such as Alzheimer's disease (AD). Accordingly, oxidation of KCNB1 channels was exacerbated in the brain of a triple transgenic mouse model of AD (3xTg-AD). The C73A variant protected neuronal cells from apoptosis induced by incubation with ␤-amyloid peptide (A␤ 1-42 ). In an invertebrate model (Caenorhabditis elegans) that mimics aspects of AD, a C73A-KCNB1 homolog (C113S-KVS-1) protected specific neurons from apoptotic death induced by ectopic expression of human A␤ 1-42 . Together, these data underscore a novel mechanism of toxicity in neurodegenerative disease. IntroductionPotassium (K ϩ ) channels are a diverse and ubiquitous family of ion-channels that operate in nonexcitable and excitable cells. K ϩ channels are essential for the function of the nervous system where they modulate the shape and frequency of action potentials and consequently, neurotransmitter release. As such, conditions that result in the impairment of K ϩ channels have the potential to cause neuronal dysfunction by affecting the excitability of the cell, which is intrinsically dependent on these proteins. For example, mutations in KCNQ2, KCNQ3, KCNMA1, KCNA1 and KCNC3 genes which lead to the synthesis of mutants with defective properties have been identified in patients affected by epilepsy, ataxia and episodic ataxia type 1 (for review, see Kullmann, 2002). In addition to genetic predisposition, acquired impairment of K ϩ channel's function can lead to neurological diseases, such as, acquired neuromyotonia, limbic encephalitis, and Morvan's syndrome (for review, see Vernino, 2007).Oxygen metabolism leads to the synthesis of reactive and thus potentially toxic molecules known as reactive oxygen species (ROS). The increase in unbuffered ROS levels in a cell, a phenomenon commonly referred to as oxidative stress, is thought to cause significant cellular damage and to contribute to cellular aging (Harman, 1956). Moreover, oxidative stress is elevated in neuropathies such as Alzheimer's disease (AD) (for review, see Lin and Beal, 2006). Oxidative damage occurs early in AD, before the onset of significant plaque formation (Nunomura et al., 2001;Praticò et al., 2001;Reddy et al., 2004), and consequent...

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Altered oxidant-mediated intraneuronal zinc mobilization in a triple transgenic mouse model of Alzheimer’s disease

Cited by 44 publications

References 42 publications

Neuroprotective features of carnosine in oxidative driven diseases

Neuroprotective features of carnosine in oxidative driven diseases

Oxidative stress in Alzheimer’s disease

Toxic Role of K⁺Channel Oxidation in Mammalian Brain

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Altered oxidant-mediated intraneuronal zinc mobilization in a triple transgenic mouse model of Alzheimer’s disease

Cited by 44 publications

References 42 publications

Neuroprotective features of carnosine in oxidative driven diseases

Neuroprotective features of carnosine in oxidative driven diseases

Oxidative stress in Alzheimer’s disease

Toxic Role of K+Channel Oxidation in Mammalian Brain

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Toxic Role of K⁺Channel Oxidation in Mammalian Brain