Causes of oxidative stress in Alzheimer disease

Zhu, Xiongwei; Su, Bo; Wang, Xinglong; Smith, Mark A.; Perry, George

doi:10.1007/s00018-007-7218-4

Cited by 310 publications

(230 citation statements)

References 121 publications

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“…23 These 8 This oxidative stress affects the cholinergic transmission system, which explains the underlying cholinergic deficit in AD patients. 24 Several efforts have been made to elucidate the mechanism of ROS production due to the interaction of Ab fibrils and Cu 21 ; 8 however, the effect of Cu 21 and other metals on the oligomerization process is not well defined, and different authors have reported contradictory results.…”

Section: Discussionmentioning

confidence: 99%

“…6,7 The interaction between Ab-fibrils and Cu 21 is important not only because of its role in amyloidosis but also because it has been associated with the generation of oxidative stress. 8 Therefore, several experimental and computational methods have focused on the analysis of the interaction between Ab 1242 and Cu 21 . However, although some research has shown that Ab contains amino acid residues that can interact with Cu 21 , 9 the effects of these interactions with respect to the Ab 1242 oligomerization process have been contradictory.…”

Section: Introductionmentioning

confidence: 99%

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In silico and in vitro studies to elucidate the role of Cu²⁺ and galanthamine as the limiting step in the amyloid beta (1–42) fibrillation process

et al. 2013

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The formation of fibrils and oligomers of amyloid beta (Aβ) with 42 amino acid residues (Aβ1–42) is the most important pathophysiological event associated with Alzheimer's disease (AD). The formation of Aβ fibrils and oligomers requires a conformational change from an α‐helix to a β‐sheet conformation, which is encouraged by the formation of a salt bridge between Asp 23 or Glu 22 and Lys 28. Recently, Cu2+ and various drugs used for AD treatment, such as galanthamine (Reminyl®), have been reported to inhibit the formation of Aβ fibrils. However, the mechanism of this inhibition remains unclear. Therefore, the aim of this work was to explore how Cu2+ and galanthamine prevent the formation of Aβ1–42 fibrils using molecular dynamics (MD) simulations (20 ns) and in vitro studies using fluorescence and circular dichroism (CD) spectroscopies. The MD simulations revealed that Aβ1–42 acquires a characteristic U‐shape before the α‐helix to β‐sheet conformational change. The formation of a salt bridge between Asp 23 and Lys 28 was also observed beginning at 5 ns. However, the MD simulations of Aβ1−42 in the presence of Cu2+ or galanthamine demonstrated that both ligands prevent the formation of the salt bridge by either binding to Glu 22 and Asp 23 (Cu2+) or to Lys 28 (galanthamine), which prevents Aβ1−42 from adopting the U‐characteristic conformation that allows the amino acids to transition to a β‐sheet conformation. The docking results revealed that the conformation obtained by the MD simulation of a monomer from the 1Z0Q structure can form similar interactions to those obtained from the 2BGE structure in the oligomers. The in vitro studies demonstrated that Aβ remains in an unfolded conformation when Cu2+ and galanthamine are used. Then, ligands that bind Asp 23 or Glu 22 and Lys 28 could therefore be used to prevent β turn formation and, consequently, the formation of Aβ fibrils.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

In silico and in vitro studies to elucidate the role of Cu²⁺ and galanthamine as the limiting step in the amyloid beta (1–42) fibrillation process

et al. 2013

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“…Oxidative stress has often been emphasized as probably the earliest feature in the AD brain with implications as an important mediator in the onset, progression and pathogenesis of the disease (Götz et al, 1994;Zhu et al 2007). The interpretation of the results of clinical trials which tested the therapeutic activity of various antioxidants is difficult due to a lack of specificity of such drugs to neural mitochondria where ROS production is most significant, and due to the additional activities these drugs may possess such as anti-inflammatory and iron-chelating ones (Bonda et al 2010;Wollen 2010).…”

Section: Compounds With Predominant Antioxidative Activity Often Accmentioning

confidence: 99%

What have we learned from the streptozotocin-induced animal model of sporadic Alzheimer’s disease, about the therapeutic strategies in Alzheimer’s research

et al. 2012

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“…OS is mediated by the formation of free radicals (hydroxyl radicals) due to electron transfer occurring when copper shifts its valency from the divalent (Cu 2 þ ) to monovalent (Cu þ ) state. 15 As a result, copper has been shown to cause oxidative damage to proteins, lipids, and nucleic acids. [16][17][18][19][20] Further, increased levels of hydroperoxides have been reported in a human glial cell line treated with excess copper.…”

mentioning

confidence: 99%

The mitochondrial permeability transition, and oxidative and nitrosative stress in the mechanism of copper toxicity in cultured neurons and astrocytes

Reddy

Rao

Norenberg

2008

Laboratory Investigation

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Copper is an essential element and an integral component of various enzymes. However, excess copper is neurotoxic and has been implicated in the pathogenesis of Wilson's disease, Alzheimer's disease, prion conditions, and other disorders. Although mechanisms of copper neurotoxicity are not fully understood, copper is known to cause oxidative stress and mitochondrial dysfunction. As oxidative stress is an important factor in the induction of the mitochondrial permeability transition (mPT), we determined whether mPT plays a role in copper-induced neural cell injury. Cultured astrocytes and neurons were treated with 20 mM copper and mPT was measured by changes in the cyclosporin A (CsA)-sensitive inner mitochondrial membrane potential (DCm), employing the potentiometric dye TMRE. In astrocytes, copper caused a 36% decrease in the DCm at 12 h, which decreased further to 48% by 24 h and remained at that level for at least 72 h. Cobalt quenching of calcein fluorescence as a measure of mPT similarly displayed a 45% decrease at 24 h. Pretreatment with antioxidants significantly blocked the copper-induced mPT by 48-75%. Copper (24 h) also caused a 30% reduction in ATP in astrocytes, which was completely blocked by CsA. Copper caused death (42%) in astrocytes by 48 h, which was reduced by antioxidants (35-60%) and CsA (41%). In contrast to astrocytes, copper did not induce mPT in neurons. Instead, it caused early and extensive death with a concomitant reduction (63%) in ATP by 14 h. Neuronal death was prevented by antioxidants and nitric oxide synthase inhibitors but not by CsA. Copper increased protein tyrosine nitration in both astrocytes and neurons. These studies indicate that mPT, and oxidative and nitrosative stress represent major factors in copper-induced toxicity in astrocytes, whereas oxidative and nitrosative stress appears to play a major role in neuronal injury.

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Causes of oxidative stress in Alzheimer disease

Cited by 310 publications

References 121 publications

In silico and in vitro studies to elucidate the role of Cu²⁺ and galanthamine as the limiting step in the amyloid beta (1–42) fibrillation process

In silico and in vitro studies to elucidate the role of Cu²⁺ and galanthamine as the limiting step in the amyloid beta (1–42) fibrillation process

What have we learned from the streptozotocin-induced animal model of sporadic Alzheimer’s disease, about the therapeutic strategies in Alzheimer’s research

The mitochondrial permeability transition, and oxidative and nitrosative stress in the mechanism of copper toxicity in cultured neurons and astrocytes

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Causes of oxidative stress in Alzheimer disease

Cited by 310 publications

References 121 publications

In silico and in vitro studies to elucidate the role of Cu2+ and galanthamine as the limiting step in the amyloid beta (1–42) fibrillation process

In silico and in vitro studies to elucidate the role of Cu2+ and galanthamine as the limiting step in the amyloid beta (1–42) fibrillation process

What have we learned from the streptozotocin-induced animal model of sporadic Alzheimer’s disease, about the therapeutic strategies in Alzheimer’s research

The mitochondrial permeability transition, and oxidative and nitrosative stress in the mechanism of copper toxicity in cultured neurons and astrocytes

Contact Info

Product

Resources

About

In silico and in vitro studies to elucidate the role of Cu²⁺ and galanthamine as the limiting step in the amyloid beta (1–42) fibrillation process

In silico and in vitro studies to elucidate the role of Cu²⁺ and galanthamine as the limiting step in the amyloid beta (1–42) fibrillation process