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1.
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
2.
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
3.
Ramesh JL Kandimalla Willayat Yousuf Wani Binukumar BK Kiran Dip Gill 《Journal of biomedical science》2012,19(1):2
Background
One of the pathological hallmarks of Alzheimer's disease (AD) is the deposition of the ~4 kDa amyloid β protein (Aβ) within lesions known as senile plaques. Aβ is also deposited in the walls of cerebral blood vessels in many cases of AD. A substantial proportion of the Aβ that accumulates in the AD brain is deposited as Amyloid, which is highly insoluble, proteinaceous material with a β-pleated-sheet conformation and deposited extracellularly in the form of 5-10 nm wide straight fibrils. As γ-secretase catalyzes the final cleavage that releases the Aβ42 or 40 from amyloid β -protein precursor (APP), therefore, it is a potential therapeutic target for the treatment of AD. γ-Secretase cleavage is performed by a high molecular weight protein complex containing presenilins (PSs), nicastrin, Aph-1 and Pen-2. Previous studies have demonstrated that the presenilins (PS1 and PS2) are critical components of a large enzyme complex that performs γ-secretase cleavage. 相似文献4.
Frozza RL Horn AP Hoppe JB Simão F Gerhardt D Comiran RA Salbego CG 《Neurochemical research》2009,34(2):295-303
Accumulation of the neurotoxic amyloid β-peptide (Aβ) in the brain is a hallmark of Alzheimer’s disease (AD). Several synthetic
Aβ peptides have been used to study the mechanisms of toxicity. Here, we sought to establish comparability between two commonly
used Aβ peptides Aβ1-42 and Aβ25-35 on an in vitro model of Aβ toxicity. For this purpose we used organotypic slice cultures
of rat hippocampus and observed that both Aβ peptides caused similar toxic effects regarding to propidium iodide uptake and
caspase-3 activation. In addition, we also did not observe any effect of both peptides on Akt and PTEN phosphorylation; otherwise
the phosphorylation of GSK-3β was increased. Although further studies are necessary for understanding mechanisms underlying
Aβ peptide toxicity, our results provide strong evidence that Aβ1-42 and the Aβ25-35 peptides induce neural injury in a similar
pattern and that Aβ25-35 is a convenient tool for the investigation of neurotoxic mechanisms involved in AD. 相似文献
5.
The amyloid β-protein (Aβ) deposited in Alzheimer’s disease (AD), the most common form of dementia in the elderly, is a secreted
proteolytic product of the amyloid β-protein precursor (APP). Generation of Aβ from the APP requires two sequential proteolytic
events, β-secretase cleavage to generate the amino terminus, followed by γ-secretase cleavage to generate the carboxyl terminus.
Because this process is a central event in the pathogenesis of AD, γ-secretase is believed to be an excellent therapeutic
target. γ-Secretase activity has been demonstrated to be membrane-associated, with the cleavage site primarily determined
by the location of the substrate with respect to the membrane. It has also been shown that this unusual proteolytic activity
not only occurs for APP, but also for proteins involved in morphogenic processes or cell proliferation and differentiation
such as Notch and ErbB4. Thus far, all γ-secretase substrates are involved in some form of nuclear signaling. These recent
findings have important implications for the development of pharmacological interventions that target γ-secretase. 相似文献
6.
Alzheimer's Disease (AD), the most common age-related neurodegenerative disorder, is characterized by progressive cognitive
decline, synaptic loss, the formation of extracellular β-amyloid plaques and intracellular neurofibrillary tangles, and neuronal
cell death. Despite the massive neuronal loss in the ‘late stage’ of disease, dendritic spine loss represents the best pathological
correlate to the cognitive impairment in AD patients. The ‘amyloid hypothesis’ of AD recognizes the Aβ peptide as the principal
player in the pathological process. Many lines of evidence point out to the neurotoxicity of Aβ, highlighting the correlation
between soluble Aβ oligomer accumulation, rather than insoluble Aβ fibrils and disease progression. Pathological increase
of Aβ in AD brains, resulting from an imbalance between its production, aggregation and clearance, might target mitochondrial
function promoting a progressive synaptic impairment. The knowledge of the exact mechanisms by which Aβ peptide impairs neuronal
function will help us to design new pharmacological tools for preventing AD neurodegeneration. 相似文献
7.
The role of cholesterol in pathogenesis of Alzheimer's disease: dual metabolic interaction between amyloid beta-protein and cholesterol 总被引:8,自引:0,他引:8
Michikawa M 《Molecular neurobiology》2003,27(1):1-12
The implication that cholesterol plays an essential role in the pathogenesis of Alzheimer’s disease (AD) is based on the 1993
finding that the presence of apolipoprotein E (apoE) allele ε4 is a strong risk factor for developing AD. Since apoE is a
regulator of lipid metabolism, it is reasonable to assume that lipids such as cholesterol are involved in the pathogenesis
of AD. Recent epidemiological and biochemical studies have strengthened this assumption by demonstrating the association between
cholesterol and AD, and by proving that the cellular cholesterol level regulates synthesis of amyloid β-protein (Aβ). Yet
several studies have demonstrated that oligomeric Aβ affects the cellular cholesterol level, which in turn has a variety of
effects on AD-related pathologies, including modulation of tau phosphorylation, synapse formation and maintenance of its function,
and the neurodegenerative process. All these findings suggest that the involvement of cholesterol in the pathogenesis of AD
is dualistic—it is involved in Aβ generation and in the amyloid cascade, leading to disruption of synaptic plasticity, promotion
of tau phosphorylation, and eventual neurodegeneration. This review article describes recent findings that may lead to the
development of a strategy for AD prevention by decreasing the cellular cholesterol level, and also focuses on the impact of
Aβ on cholesterol metabolism in AD and mild cognitive impairment (MCI), which may result in promotion of the amyloid cascade
at later stages of the AD process. 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.
Pathogenesis of Alzheimer’s disease (AD), which is characterised by accumulation of extracellular deposits of β-amyloid peptide
(Aβ) in the brain, has recently been linked to vascular disorders such as ischemia and stroke. Aβ is constantly produced in
the brain from amyloid precursor protein (APP) through its cleavage by β- and γ-secretases and certain Aβ species are toxic
for neurones. The brain has an endogenous mechanism of Aβ removal via proteolytic degradation and the zinc metalloproteinase
neprilysin (NEP) is a critical regulator of Aβ concentration. Down-regulation of NEP could predispose to AD. By comparing
the effects of hypoxia and oxidative stress on expression and activity of the Aβ-degrading enzyme NEP in human neuroblastoma
NB7 cells and rat primary cortical neurones we have demonstrated that hypoxia reduced NEP expression at the protein and mRNA
levels as well as its activity. On contrary in astrocytes hypoxia increased NEP mRNA expression.
Special issue dedicated to Dr. Moussa Youdim. 相似文献
10.
The physiological relationship between brain cholesterol content and the action of amyloid β (Aβ) peptide in Alzheimer’s disease (AD) is a highly controversially discussed topic. Evidences for modulations of the Aβ/membrane interaction induced by plasma membrane cholesterol have already been observed. We have recently reported that Aβ(25–35) is capable of inserting in lipid membranes and perturbing their structure. Applying neutron diffraction and selective deuteration, we now demonstrate that cholesterol alters, at the molecular level, the capability of Aβ(25–35) to penetrate into the lipid bilayers; in particular, a molar weight content of 20% of cholesterol hinders the intercalation of monomeric Aβ(25–35) completely. At very low cholesterol content (about 1% molar weight) the location of the C-terminal part of Aβ(25–35) has been unequivocally established in the hydrocarbon region of the membrane, in agreement with our previous results on pure phospholipids membrane. These results link a structural property to a physiological and functional behavior and point to a therapeutical approach to prevent the AD by modulation of membrane properties. 相似文献
11.
The Alzheimer’s disease neurotoxic amyloid-β (Aβ) peptide is derived from the larger amyloid precursor protein (APP) and is
the principal component of the senile plaques in Alzheimer’s disease (AD) brains. This mechanism by which Aβ mediates neurotoxicity
or neuronal dysfunction is not fully resolved. This review will outline some of the key determinants that modulate Aβ’s activity
and the cellular pathways and mechanisms involved. 相似文献
12.
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
13.
Aggregation of the amyloid β-peptide (Aβ) into insoluble fibrils is a key pathological event in Alzheimer’s disease. Cu(II)
and Zn(II) ions were reported to be able to induce Aβ aggregation at nearly physiological concentrations in vitro. In this
study, the binding modes of Cu(II) and Zn(II) in this process were explored by molecular modeling. In the pre-associated Aβ,
Nτ atom of imidazole ring of His14, O atom of carbonyl of main-chain and two O atoms of water occupied the four ligand positions
of the complex. While in the aggregated form of Aβ, the His13(N)–Metals–His14(N) bridges were formed through metal cross-linking
action. These results would be helpful to put insight on revealing the formation mechanism of pathogenic Aβ aggregates in
brain. 相似文献
14.
Vieira MN Figueroa-Villar JD Meirelles MN Ferreira ST De Felice FG 《Cell biochemistry and biophysics》2006,44(3):549-553
Protein amyloid aggregation is associated with a number of important human pathologies, but the precise mechanisms underlying
the toxicity of amyloid aggregates are still incompletely understood. In this context, drugs capable of blocking or interfering
with the aggregation of amyloidogenic proteins should be considered in strategies aimed at the development of novel therapeutic
agents. Human lysozyme variants have been shown to form massive amyloid deposits in the livers and kidneys of individuals
affected by hereditary systemic amyloidosis. Currently, there are no clinical treatments available to prevent or reverse formation
of such amyloid deposits. We have recently described a number of di- and trisubstituted aromatic compounds that block the
formation of soluble oligomers and amyloid fibrils of the β-amyloid peptide (Aβ) and protect hippocampal neurons in culture
from Aβ-induced toxicity. Here, we show that some of those compounds inhibit the formation and disrupt preformed amyloid fibrils
from both human and hen egg white lysozyme. These results suggest that these small molecule compounds may serve as prototypes
for the development of drugs for the prevention or treatment of different types of amyloidoses. 相似文献
15.
Recently, increasing evidence has linked high cholesterol to the pathogenesis of Alzheimer’s disease (AD), suggesting that
cholesterol may be a target for developing new compounds to prevent or treat AD. Plant sterols, a group of sterols enriched
in plant oils, nuts, and avocados, have the structure very similar to that of cholesterol, and have been widely used to reduce
blood cholesterol. Due to their cholesterol-lowering property, plant sterols such as β-sitosterol may also influence cholesterol-depending
functions including its role in AD development. Using human platelets, a type of peripheral blood cells containing the most
circulating amyloid precursor protein (APP), this study investigated the effect of β-sitosterol on high cholesterol-induced
secretion of β amyloid protein (Aβ). It was found that β-sitosterol effectively inhibited high cholesterol-driven platelet
Aβ release. In addition, β-sitosterol prevented high cholesterol-induced increase of activities of β- and γ-secretase, two
APP cleaving enzymes to generate Aβ. Additional experiments showed that high cholesterol up-regulated lipid raft cholesterol.
This effect of cholesterol could be suppressed by β-sitosterol. These findings suggest that β-sitosterol is able to inhibit
high cholesterol-induced Aβ release probably through maintenance of membrane cholesterol homeostasis. Given that dietary plant
sterols have the potential of penetrating the blood–brain barrier (BBB), these data suggest that plant sterols such as β-sitosterol
may be useful in AD prevention. 相似文献
16.
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
17.
Yang HQ Sun ZK Zhao YX Pan J Ba MW Lu GQ Ding JQ Chen HZ Chen SD 《Neurochemical research》2009,34(3):528-535
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized clinically by progressive impairment of memory and
cognition. Previous data have shown that beta-amyloid (Aβ) cascade plays a central role in AD pathophysiology and thus drugs
regulate amyloid precursor protein (APP) metabolism may have therapeutic potential. Here the effects of PMS777, a new cholinesterase
inhibitor with anti-platelet activated factor activity, on APP processing were investigated. Using SH-SY5YAPP695 cells, it showed that PMS777 treatment caused significant decreased secretion of sAPPα into the conditioned media without
affecting cellular holoAPP synthesis. When PC12 cells were incubated with PMS777, the same effect was observed. The data also
indicated that 10 μM PMS777 incubation decreased the release of Aβ42 into the cell media as compared with vehicle group in
SH-SY5YAPP695 cells. Pretreatment of cells with M-receptor scopolamine antagonized the decreased secretion of sAPPα induced by PMS777,
but N-receptor α-bungarotoxin pretreatment did not have such an effect. These results indicated that PMS777 could modulate
APP processing in vitro and that decreasing Aβ generation might demonstrate its therapeutic potential in AD. 相似文献
18.
The pathologic lesions of Alzheimer’s disease (AD) are characterized by accumulation of protein aggregates consisting of intracellular
or extracellular misfolded proteins. The amyloid-β (Aβ) protein accumulates extracellularly in senile plaques and cerebral
amyloid angiopathy, whereas the hyperphosphorylated tau protein accumulates intracellularly as neurofibrillary tangles. “Professional
chaperones”, such as the heat shock protein family, have a function in the prevention of protein misfolding and subsequent
aggregation. “Amateur” chaperones, such as apolipoproteins and heparan sulfate proteoglycans, bind amyloidogenic proteins
and may affect their aggregation process. Professional and amateur chaperones not only colocalize with the pathological lesions
of AD, but may also be involved in conformational changes of Aβ, and in the clearance of Aβ from the brain via phagocytosis
or active transport across the blood–brain barrier. Thus, both professional and amateur chaperones may be involved in the
aggregation, accumulation, persistence, and clearance of Aβ and tau and in other Aβ-associated reactions such as inflammation
associated with AD lesions, and may, therefore, serve as potential targets for therapeutic intervention. 相似文献
19.
Alzheimer’s disease (AD) is a significant contributor to cognitive decline and is responsible for about half of the cases
of dementia in later life. Although exact etiology of AD is not known, however, many risk factors for AD are identified. Anesthesia
for elderly patients is considered as a risk factor in AD as they frequently experience deterioration in cognitive function
with long exposure to anesthetics during surgery. Inhaled anesthetic agents remain the mainstay for patients undergoing major
surgical operations. This study using multidimensional NMR spectroscopy provides the first direct evidence in vitro that inhaled
anesthetic, halothane specifically interacts with Aβ40 and Aβ42 peptide. Halothane induces structural alternation of Aβ peptide
from soluble monomeric α-helical form to oligomeric β-sheet conformation, which may hasten the onset of AD. Aβ42 is more prone
to oligomerization compared to Aβ40 in the presence of halothane. The molecular mechanism of halothane induced structural
alternation of Aβ peptide is discussed.
An erratum to this article can be found at 相似文献
20.