共查询到20条相似文献,搜索用时 15 毫秒
1.
Feda E Ali Frances Separovic Colin J Barrow Robert A Cherny Fiona Fraser Ashley I Bush Colin L Masters Kevin J Barnham 《Journal of peptide science》2005,11(6):353-360
Metal-catalysed oxidation (MCO) may play a causative role in the pathogenesis of Alzheimer's disease (AD). Amyloid beta peptide (Abeta), the major biomarker of AD, in the presence of copper ions reduces Cu(2+) to Cu(+) and catalyses the formation of H(2)O(2) that subsequently induces radicals through Fenton chemistry. Abeta is also subject to attack by free radicals, where the presence of Cu(2+) in conjunction with H(2)O(2) catalyses oxygenation, primarily at the methionine sulfur atom. This work investigates MCO of Abeta, to gain further insight into the role of oxidative stress in AD. By combining a fluorescence assay with gel electrophoresis to monitor MCO reactions of Abeta (1-28) in the presence and absence of methionine it was determined that methionine can both protect some residues against MCO and promote the oxidation of Tyr(10) specifically. Electrospray ionization mass spectrometric analysis of methionine MCO products indicated the formation of methionine sulfoxide, methionine sulfone and related hydroxylated products. Similar products could be formed from the oxidation of Met(35) of Abeta and may relate to changes in properties of the peptide following MCO. 相似文献
2.
Ferrera P Mercado-Gómez O Silva-Aguilar M Valverde M Arias C 《Neurochemical research》2008,33(8):1509-1517
Alterations in brain cholesterol concentration and metabolism seem to be involved in Alzheimer’s disease (AD). In fact, several
experimental studies have reported that modification of cholesterol content can influence the expression of the amyloid precursor
protein (APP) and amyloid β peptide (Aβ) production. However, it remains to be determined if changes in neuronal cholesterol
content may influence the toxicity of Aβ peptides and the mechanism involved. Aged mice, AD patients and neurons exposed to
Aβ, show a significant increase in membrane-associated oxidative stress. Since Aβ is able to promote oxidative stress directly
by catalytically producing H2O2 from cholesterol, the present work analyzed the effect of high cholesterol incorporated into human neuroblastoma cells in
Aβ-mediated neurotoxicity and the role of reactive oxygen species (ROS) generation. Neuronal viability was studied also in
the presence of 24S-hydroxycholesterol, the main cholesterol metabolite in brain, as well as the potential protective role
of the lipophilic statin, lovastatin.
Special issue article in honor of Dr. Ricardo Tapia. 相似文献
3.
Jesudason EP Masilamoni JG Ashok BS Baben B Arul V Jesudoss KS Jebaraj WC Dhandayuthapani S Vignesh S Jayakumar R 《Molecular and cellular biochemistry》2008,311(1-2):145-156
Aβ amyloid peptide is believed to induce oxidative stress leading to inflammation, which is postulated to play a significant
role in the toxicity of Alzheimer’s disease (AD). This study was designed to investigate the inhibitory effects of dl-α lipoic acid (LA), a potential free radical scavenger, on oxidative vulnerability induced by intraperitoneal injection of
Aβ25–35 amyloid fibrils in mice. Mice were divided into three groups: control, Aβ amyloid toxicity induced (AT), and LA treated (ATL).
Blood Plasma was separated, liver, spleen and brain were dissected and analysis of oxidants, antioxidants, ATPases, glial
fibrillary acidic protein (GFAP) and nuclear factor kappa-B (NFκB) were carried out. Results show biochemical parameters such
as reactive oxygen species (ROS) and lipid peroxidation (LPO) were significantly lowered (P < 0.05) and levels of antioxidants and ATPase (P < 0.05) were significantly increased (P < 0.05) in hepatocytes, splenocytes and astrocytes of the ATL group. Moreover, our histological results revealed a decreased
GFAP immunoreactivity in the neocortical region and NFκB immunoreactivity in neocortex, liver and spleen. This study reiterates
LA as a potent free radical scavenger to combat oxidative vulnerability in the treatment for Aβ amyloid toxicity. 相似文献
4.
Alzheimer disease (AD) is an age-related neurodegenerative disorder, characterized histopathologically by the presence of
senile plaques (SP), neurofibrillary tangles and synapse loss in selected brain regions. Positron emission tomography (PET)
studies of glucose metabolism revealed decreased energetics in brain of subjects with AD and arguably its earliest form, mild
cognitive impairment (MCI), and this decrease correlated with brain structural studies using MRI. The main component of senile
plaques is amyloid beta-peptide (Aβ), a 40–42 amino acid peptide that as oligomers is capable of inducing oxidative stress
under both in vitro and in vivo conditions and is neurotoxic. In the mitochondria isolated from AD brain, Aβ oligomers that
correlated with the reported increased oxidative stress markers in AD have been reported. The markers of oxidative stress
have been localized in the brain regions of AD and MCI that show pathological hallmarks of this disease, suggesting the possible
role of Aβ in the initiation of the free-radical mediated process and consequently to the build up oxidative stress and AD
pathogenesis. Using redox proteomics our laboratory found a number of oxidatively modified brain proteins that are directly
in or are associated with the mitochondrial proteome, consistent with a possible involvement of the mitochondrial targeted
oxidatively modified proteins in AD progression or pathogenesis. The precise mechanistic link between mitochondrial oxidative
damage and role of oligomeric Aβ has not been explicated. In this review, we discuss the role of the oxidation of mitochondria-relevant
brain proteins to the pathogenesis and progression of AD. 相似文献
5.
Ya Hui Hung Ashley I. Bush Robert Alan Cherny 《Journal of biological inorganic chemistry》2010,15(1):61-76
Alzheimer’s disease (AD) is the most common form of neurodegenerative disease. The brain is particularly vulnerable to oxidative
damage induced by unregulated redox-active metals such as copper and iron, and the brains of AD patients display evidence
of metal dyshomeostasis and increased oxidative stress. The colocalisation of copper and amyloid β (Aβ) in the glutamatergic
synapse during NMDA-receptor-mediated neurotransmission provides a microenvironment favouring the abnormal interaction of
redox-potent Aβ with copper under conditions of copper dysregulation thought to prevail in the AD brain, resulting in the
formation of neurotoxic soluble Aβ oligomers. Interactions between Aβ oligomers and copper can further promote the aggregation
of Aβ, which is the core component of extracellular amyloid plaques, a central pathological hallmark of AD. Copper dysregulation
is also implicated in the hyperphosphorylation and aggregation of tau, the main component of neurofibrillary tangles, which
is also a defining pathological hallmark of AD. Therefore, tight regulation of neuronal copper homeostasis is essential to
the integrity of normal brain functions. Therapeutic strategies targeting interactions between Aβ, tau and metals to restore
copper and metal homeostasis are discussed. 相似文献
6.
Alicia M. Pickrell Hirokazu Fukui Carlos T. Moraes 《Journal of bioenergetics and biomembranes》2009,41(5):453-456
The multiple dysfunctional changes associated with a brain affected with Alzheimer’s disease (AD) makes the understanding
of primary pathogenic mechanisms challenging. Mitochondrial dysfunction has been associated with almost every neurodegenerative
disease and neurodegenerative-related event. Alzheimer’s disease is no exception with data suggesting mitochondrial malfunctions
ranging from improper organelle dynamics, defective oxidative phosphorylation (OXPHOS), oxidative stress, and harmful beta
amyloid (Aβ) associations with the mitochondria. A major change often associated with AD is impairment of the electron transport
chain at complex IV: cytochrome c oxidase (COX). This mini-review concentrates on recent work by our group that sheds light on the role COX deficiency plays
in the pathophysiology of AD using a transgenic mouse model. Results suggest that neuronal COX deficiency does not increase
oxidative stress and nor increases amyloidal formations in vivo. Conclusions from this work also suggest that Aβ formation is a cause of COX deficiency as opposed to the consequence. 相似文献
7.
Anna Colell Anna Fernández José C. Fernández-Checa 《Journal of bioenergetics and biomembranes》2009,41(5):417-423
The molecular mechanisms of Alzheimer’s disease (AD) are not fully understood. Extensive evidence from experimental models
has involved the overgeneration and accumulation of toxic amyloid β peptides (Aβ) in the onset and progression of the disease.
The amyloidogenic processing of amyloid precursor protein into pathogenic Aβ fragments is thought to occur in specific domains
of the plasma membrane and favored by cholesterol enrichment. Intracellular Aβ accumulation is known to induce oxidative stress,
predominantly via mitochondria targeting of toxic Aβ. Recent evidence using mouse models of cholesterol loading has demonstrated
that the specific mitochondrial cholesterol pool sensitizes neurons to Aβ-induced oxidant cell death and caspase-independent
apoptosis due to selective mitochondrial GSH (mGSH) depletion induced by cholesterol-mediated perturbation of mitochondrial
membrane dynamics. mGSH replenishment by permeable precursors such as glutathione ethyl ester protected against Aβ-mediated
neurotoxicity and inflammation. Thus, these novel data expand the pathogenic role of cholesterol in AD indicating that in
addition to fostering Aβ generation, mitochondrial cholesterol determines Aβ neurotoxicity via mGSH regulation. 相似文献
8.
Sundaram RK Kasinathan C Stein S Sundaram P 《International journal of peptide research and therapeutics》2012,18(2):99-106
Alzheimer’s disease (AD), a debilitating neurodegenerative disease is caused by aggregation and accumulation of a 39–43 amino
acid peptide (amyloid β or Aβ) in brain parenchyma and cerebrovasculature. The rational approach would be to use drugs that
interfere with Aβ–Aβ interaction and disrupt polymerization. Peptide ligands capable of binding to the KLVFF (amino acids
16–20) region in the Aβ molecule have been investigated as possible drug candidates. Retro-inverso (RI) peptide of this pentapeptide,
ffvlk, has been shown to bind artificial fibrils made from Aβ with moderate affinity. We hypothesized that a ‘detox gel’, which
is synthesized by covalently linking a tetrameric version of RI peptide ffvlk to poly(ethylene glycol) polymer chains will act like a ‘sink’ to capture Aβ peptides from the surrounding environment. We
previously demonstrated that this hypothesis works in an in vitro system. The present study extended this hypothesis to an
in vivo mouse model of AD and determined the therapeutic effect of our detox gel. We injected detox gel subcutaneously to
AD model mice and analyzed brain levels of Aβ-42 and improvement in memory parameters. The results showed a reduction of brain
amyloid burden in detox gel treated mice. Memory parameters in the treated mice improved. No undesirable immune response was
observed. The data strongly suggest that our detox gel can be used as an effective therapy to deplete brain Aβ levels. Considering
recent abandonment of failed antibody based therapies, our detox gel appears to have the advantage of being a non-immune based
therapy. 相似文献
9.
Akasaka-Manya K Manya H Sakurai Y Wojczyk BS Spitalnik SL Endo T 《Glycoconjugate journal》2008,25(8):775-786
Alteration of glycoprotein glycans often changes various properties of the glycoprotein. To understand the significance of
N-glycosylation in the pathogenesis of early-onset familial Alzheimer’s disease (AD) and in β-amyloid (Aβ) production, we examined
whether the mutations in the amyloid precursor protein (APP) gene found in familial AD affect the N-glycans on APP. We purified the secreted forms of wild-type and mutant human APPs (both the Swedish type and the London type)
produced by transfected C17 cells and determined the N-glycan structures of these three recombinant APPs. Although the major N-glycan species of the three APPs were similar, both mutant APPs contained higher contents of bisecting N-acetylglucosamine and core-fucose residues as compared to wild-type APP. These results demonstrate that familial AD mutations
in the polypeptide backbone of APP can affect processing of the attached N-glycans; however, whether these changes in N-glycosylation affect Aβ production remains to be established.
Keiko Akasaka-Manya and Hiroshi Manya contributed equally to this work. 相似文献
10.
Nuclear factor erythroid 2-related factor 2 (Nrf2) coordinates the up-regulation of cytoprotective genes via the antioxidant
response element (ARE). There is significant evidence that oxidative stress is a critical event in the pathogenesis of AD.
Considering the protective role of Nrf2 against oxidative injury, we studied to determine whether in vivo toxicity of amyloid
β (Aβ) can be attenuated by tBHQ, an Nrf2 stabilizer, Using an Aβ injection model. We demonstrated that pre-activation of
endogenous Nrf2 by tBHQ attenuated Aβ-induced caspase-3 expression. tBHQ enhanced GSH, decreased MDA level, and inhibited
NF-κB. This investigation provides the first documentation of tBHQ’s neuroprotective effect through decrease of Aβ accumulation
in rat brain. Our results show the involvement of Hsp-70 in this protective effect. In summary tBHQ treatment for 1 week prior
to Aβ injection protected against the oxidative damage, apoptosis and Aβ accumulation in rats. 相似文献
11.
Cryptotanshinione Inhibits β-Amyloid Aggregation and Protects Damage from β-Amyloid in SH-SY5Y Cells
The deposition of amyloid β-protein (Aβ) fibrils into plaques within the brain parenchyma and along cerebral blood vessels
is a hallmark of Alzheimer’s disease (AD). Aβ42 oligomers and fibrils cause the breakdown of neural circuits, neuronal death
and eventually dementia. Drugs that inhibit Aβ42 aggregation may be a novel direction in AD drug discovery. Cryptotanshinone
(CTS), an active component of the medicinal herb Salvia miltiorrhiza, has been shown to improve learning and memory in several
pharmacological models of AD. However, the effects of CTS on the Aβ aggregation and toxicity are unclear. The current work
shows the effectiveness of CTS on the inhibition of Aβ42 aggregation and toxicity to human neuroblastoma cells. In this study,
we demonstrated that CTS can inhibit Aβ42 spontaneous aggregation using thioflavin T fluorescence assay and transmission electron
microscopy. Furthermore, we investigated the effects of CTS on Aβ-induced oxidative cell death in cultured SH-SY5Y cells.
MTT and lactate dehydrogenase assays showed that CTS reduced the cytotoxicity induced by Aβ42. CTS also dramatically reduced
Aβ42-induced cellular apoptosis and increased level of reactive oxygen species in these cells. Our study suggests that CTS
may be useful in the inhibition or prevention of AD development and progression. 相似文献
12.
Background
Accumulation of amyloid β-peptide (Aβ) in the plaques is one of the major pathological features in Alzheimer's disease (AD). Sequential cleavage of amyloid precursor protein (APP) by β-site APP cleaving enzyme 1 (BACE-1) and γ-secretase results in the formation of Aβ peptides. Preventing Aβ formation is believed to attenuate AD progression and BACE-1 and γ-secretase are thus attractive targets for AD drug development. 相似文献13.
Marta Di Carlo 《European biophysics journal : EBJ》2010,39(6):877-888
Amyloid beta peptide (Aβ) is the major component of amyloid plaques in the brain of individuals affected by Alzheimer’s disease
(AD). The formation of the plaques is due to an overproduction of Aβ by APP processing, its precursor, and to its ability
to convert under specific conditions from its soluble form into highly ordered fibrillar aggregates. Although neuronal degeneration
occurs near the amyloid plaques, some studies have suggested that intermediates such as protofibrils or simple oligomers are
also involved in AD pathogenesis and even appear to be the more dangerous species in the onset of the pathology. Further,
toxic properties of aggregates of different size have been investigated and the obtained results support the hypothesis that
different aggregate sizes can induce different degeneration pathways. In the present review some of the knowledge about the
biochemical routes of Aβ processing and production and the relationship among Aβ and oxidative stress, metal homeostasis,
inflammatory process, and cell death are summarized. Moreover, current strategies addressing both fibrillogenesis process
and different Aβ altered biochemical pathways utilized for therapies are described. 相似文献
14.
Giuseppe D. Ciccotosto Kevin J. Barnham Robert A. Cherny Colin L. Masters Ashley I. Bush Cyril C. Curtain Roberto Cappai Deborah Tew 《International journal of peptide research and therapeutics》2003,10(5-6):413-417
Summary The amyloid β-peptide, Aβ is toxic to neurons and this toxicity plays a central role in the progression of Alzheimer's disease.
The mechanism(s) by which Aβ exerts its toxicity has been hotly debated with several theories postulated. Here we discuss
the role of oxidation of the sulfur atom of Met35 in Aβ42 (Met(O)Aβ), a modification that has significant implications for
the mechanism of Aβ toxicity. Both Met(O)Aβ and its native form display toxicity to primary neuronal cells in culture which
can be rescued by catalase, a H2O2 inhibitor and clioquinol a mild copper chelator. However both native Aβ and Met(O)Aβ differ substantially in primary and
secondary structures, solubility, ability to penetrate lipid membranes, and oligomerization profiles. It is clearly evident
that metals play an important role in the oxidation of Aβ to Met(O)Aβ via Fenton chemistry and that regulation of this pathway
has a potential therapeutic application for the regulation of Alzheimer's disease. 相似文献
15.
Nyosha Alikhani Maria Ankarcrona Elzbieta Glaser 《Journal of bioenergetics and biomembranes》2009,41(5):447-451
Several lines of evidence suggest mitochondrial dysfunction as a possible underlying mechanism of Alzheimer’s disease (AD).
Accumulation of the amyloid-β peptide (Aβ), a neurotoxic peptide implicated in the pathogenesis of AD, has been detected in
brain mitochondria of AD patients and AD transgenic mouse models. In vitro evidence suggests that the Aβ causes mitochondrial dysfunction e.g. oxidative stress, mitochondrial fragmentation and decreased
activity of cytochrome c oxidase and TCA cycle enzymes. Here we review the link between mitochondrial dysfunctions and AD.
In particular we focus on the mechanism for Aβ uptake by mitochondria and on the recently identified Aβ degrading protease
in human brain mitochondria. 相似文献
16.
Beta-amyloid peptide (Aβ), a major protein component of senile plaques, has been considered as a critical cause in the pathogenesis
of Alzheimer’s disease (AD). Modulation of the Aβ-induced neurotoxicity has emerged as a possible therapeutic approach to
ameliorate the onset and progression of AD. The present study aimed to evaluate the protective effect of isorhynchophylline,
an oxindole alkaloid isolated from a Chinese herb Uncaria rhynchophylla, on Aβ-induced neurotoxicity in cultured rat pheochromocytoma (PC12) cells. The results showed that pretreatment with isorhynchophylline
significantly elevated cell viability, decreased the levels of intracellular reactive oxygen species and malondialdehyde,
increased the level of glutathione, and stabilized mitochondrial membrane potential in Aβ25-35-treated PC12 cells. In addition, isorhynchophylline significantly suppressed the formation of DNA fragmentation and the activity
of caspase-3 and moderated the ratio of Bcl-2/Bax. These results indicate that isorhynchophylline exerts a neuroprotective
effect against Aβ25-35-induced neurotoxicity in PC12 cells, at least in part, via inhibiting oxidative stress and suppressing the mitochondrial
pathway of cellular apoptosis. 相似文献
17.
Unifying features of systemic and cerebral amyloidosis 总被引:6,自引:0,他引:6
Amyloidosis is a generic term for a group of clinically and biochemically diverse diseases that are characterized by the deposition
of an insoluble fibrillar protein in the extracellular space. Over 16 biochemically distinct amyloids are known. Despite this
diversity, all amyloids have a particular ultrastructural and tinctorial appearance, a β-pleated sheet structure, and are
codeposited with a group of amyloid-associated proteins. The most common amyloidosis is Alzheimer’s disease (AD), where Aβ
is the main component of the amyloid. Recently it has been found that Aβ exists as a normal soluble protein (sAβ) in biological
fluids. This links AD more closely to some of the systemic amyloidoses, where the amyloid precursor is found in the circulation
normally. Numerous mutations have been found in the Aβ precursor (βPP) gene, associated with familial AD. Many mutations are
also found in some of the hereditary systemic amyloidoses. For example, over 40 mutations in the transthyretin (TTR) gene
are associated with amyloid. However, both Aβ and TTR related amyloid deposition can occur with no mutation. The pathogenesis
of amyloid is complex, and appears to be associated with genetic and environmental risk factors that can be similar in the
systemic and cerebral amyloidoses. 相似文献
18.
C. Behl 《Cell and tissue research》1997,290(3):471-480
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by loss of memory and progressive decline of cognitive
abilities. Although the pathogenesis of this disease is not known and is still under intensive investigation, there are several
hypotheses which address certain aspects of the disease. This review focuses on the oxidative-stress hypothesis of AD and
on novel antioxidative approaches to an effective neuroprotection for the prevention and therapy of this neurodegenerative
disorder. The toxicity of the AD-associated amyloid β-protein (Aβ), the induction of oxidative stress by Aβ in neurons, and
potential sources of oxidative events in brain tissue are discussed.
Received: 20 February 1997 / Accepted: 9 May 1997 相似文献
19.
Luc Guilloreau Luminita Damian Yannick Coppel Honoré Mazarguil Mathias Winterhalter Peter Faller 《Journal of biological inorganic chemistry》2006,11(8):1024-1038
The aggregation of the peptide amyloid-β (Aβ) to form amyloid plaques is a key event in Alzheimer’s disease. It has been shown that CuII can bind to soluble Aβ and influence its aggregation properties. Three histidines and the N-terminal amine have been proposed to be involved in its coordination. Here, for the first time, we show isothermal titration calorimetry (ITC) measurements of the CuII binding to Aβ16 and Aβ28, models of the soluble Aβ. Moreover, different spectroscopic methods were applied. The studies revealed new insights into these CuII–Aβ complexes: (1) ITC showed two CuII binding sites, with an apparent K
d of 10−7 and 10−5 M, respectively; (2) the high-affinity site has a smaller enthalpic contribution but a larger entropic contribution than the low-affinity binding site; (3) azide did not bind to CuII in the higher-affinity binding site, suggesting the absence of a weak, labile ligand; (4) azide could bind to the CuII in the low-affinity binding site in Aβ28 but not in Aβ16; (5) 1H-NMR suggests that the carboxylate of aspartic acid in position 1 is involved in the ligation to CuII in the high-affinity binding site; (6) the pK
a of 11.3 of tyrosine in position 10 was not influenced by the binding of 2 equivalents of CuII.Electronic Supplementary Material Supplementary material is available to authorized users in the online version of this article at . 相似文献
20.
The main component of senile plaques found in AD brain is amyloid β-peptide (Aβ), and the neurotoxicity and aggregation of
Aβ are associated with the formation of β-sheet structure. Experimentally, beta sheet breaker (BSB) peptide fragment Leu-Pro-Phe-Phe-Asp
(LPFFD) can combine with Aβ, which can inhibit the aggregation of Aβ. In order to explore why LPFFD can inhibit the formation
of β-sheet conformation of Aβ at atomic level, first, molecular docking is performed to obtain the binding sites of LPFFD
on the Aβ(1–42) (LPFFD/Aβ(1–42)), which is taken as the initial conformation for MD simulations. Then, MD simulations on LPFFD/Aβ(1–42)
in water are carried out. The results demonstrate that LPFFD can inhibit the conformational transition from α-helix to β-sheet
structure for the C-terminus of Aβ(1–42), which may be attributed to the hydrophobicity decreasing of C-terminus residues
of Aβ(1–42) and formation probability decreasing of the salt bridge Asp23-Lys28 in the presence of LPFFD. 相似文献