共查询到20条相似文献,搜索用时 15 毫秒
1.
Transport defects may arise in various neurodegenerative diseases from failures in molecular motors, microtubule abnormalities,
and the chaperone/proteasomal degradation pathway leading to aggresomal-lysosomal accumulations. These defects represent important
steps in the neurodegenerative cascade, although in many cases, a clear consensus has yet to be reached regarding their causal
relationship to the disease. A growing body of evidence lends support to a link between neurite transport defects in the very
early stages of many neurodegenerative diseases and alterations in the organization and dynamics of the actin cytoskeleton
initiated by filament dynamizing proteins in the ADF/cofilin family. This article focuses on cofilin, which in neurons under
stress, including stress induced by the amyloid-β (Aβ) 1–42 peptide, undergoes dephosphorylation (activation) and forms rod-shaped
actin boundles (rods). Rods inhibit transport, are sites of amyloid precursor protein accumulation, and contribute to the
pathology of Alzheimer’s disease. Because rods form rapidly in response to anoxia, they could also contribute to synaptic
deficits associated with ischemic brain injury (e.g., stroke). Surprisingly, cofilin undergoes phosphorylation (inactivation)
in hippocampal neurons treated with Aβ1–40 at high concentrations, and these neurons undergo dystrophic morphological changes, including accumulation of pretangle phosphorylated-τ. Therefore, extremes in phosphoregulation of cofilin by different forms of Aβ may explain much of the Alzheimer’s disease
pathology and provide mechanisms for synaptic loss and plaque expansion.
An erratum to this article is available at . 相似文献
2.
The Receptor for Advanced Glycation End-products (RAGE) is a multi-ligand receptor present on most cell types. Upregulation of RAGE is seen in a number of pathological states including, inflammatory and vascular disease, dementia, diabetes and various cancers. We previously demonstrated that alternative splicing of the RAGE gene is an important mechanism which regulates RAGE signaling through the production of soluble ligand decoy isoforms. However, no studies have identified any alternative splice variants within the intracellular region of RAGE, a region critical for RAGE signaling. Herein, we have cloned and characterized a novel splice variant of RAGE that has a truncated intracellular domain (RAGEΔICD). RAGEΔICD is prevalent in both human and mouse tissues including lung, brain, heart and kidney. Expression of RAGEΔICD in C6 glioma cells impaired RAGE-ligand induced signaling through various MAP kinase pathways including ERK1/2, p38 and SAPK/JNK. Moreover, RAGEΔICD significantly affected tumor cell properties through altering cell migration, invasion, adhesion and viability in C6 glioma cells. Furthermore, C6 glioma cells expressing RAGEΔICD exhibited drastic inhibition on tumorigenesis in soft agar assays. Taken together, these data indicate that RAGEΔICD represents a novel endogenous mechanism to regulate RAGE signaling. Significantly, RAGEΔICD could play an important role in RAGE related disease states through down regulation of RAGE signaling. 相似文献
3.
Eun-A Kim Hanwook Kim Jee-Yin Ahn Hoh-Gyu Hahn Key-Sun Kim Tae Ue Kim Sung-Woo Cho 《Molecules and cells》2010,30(1):51-57
We previously reported that KHG21834, a benzothiazole derivative, attenuates the beta-amyloid (Aβ)-induced degeneration of
both cortical and mesencephalic neurons in vitro. Central nervous system inflammation mediated by activated microglia is a key event in the development of neurodegenerative
disease. In this study, we show that KHG21834 suppresses inflammation-mediated cytokine upregulation. Specifically, KHG21834
induces significant reductions in the lipopolysaccharide-induced activation of microglia and production of proinflammatory
mediators such as tumor necrosis factor-α, interlukin-1β, nitric oxide, and inducible nitric oxide synthase. In addition,
KHG21834 blocks the expression of mitogen-activated protein kinases, including ERK, p38 MAPK, JNK, and Akt. In vivo intracerebroventricular infusion of KHG21834 also leads to decreases the level of interleukin-1β and tumor necrosis factor-α
in brain. These results, in combination with our previous findings on Aβ-induced degeneration, support the potential therapeutic
efficacy of KHG21834 for the treatment of neurodegenerative disorders via the targeting of key glial activation pathways. 相似文献
4.
5.
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6.
Francis C. Dehle Heath Ecroyd Ian F. Musgrave John A. Carver 《Cell stress & chaperones》2010,15(6):1013-1026
Amyloid fibril formation is associated with diseases such as Alzheimer’s, Parkinson’s, and prion diseases. Inhibition of amyloid
fibril formation by molecular chaperone proteins, such as the small heat-shock protein αB-crystallin, may play a protective
role in preventing the toxicity associated with this form of protein misfolding. Reduced and carboxymethylated κ-casein (RCMκ-CN),
a protein derived from milk, readily and reproducibly forms fibrils at physiological temperature and pH. We investigated the
toxicity of fibril formation by RCMκ-CN using neuronal model PC12 cells and determined whether the inhibition of fibril formation
altered its cell toxicity. To resolve ambiguities in the literature, we also investigated whether fibril formation by amyloid-β1–40
(Aβ1–40), the peptide associated with Alzheimer’s disease, was inhibited by αB-crystallin and if this affected the toxicity of Aβ.
To this end, either RCMκ-CN or Aβ1–40 was incubated at neutral pH to induce fibril formation before treating PC12 cells and assessing cell viability. Incubated
(fibrillar) RCMκ-CN was more toxic to PC12 cells than native RCMκ-CN with the highest level of toxicity being associated with
mature fibrils and protofibrils. Furthermore, the toxicity of RCMκ-CN was attenuated when its fibril formation was inhibited,
either through the chaperone action of αB-crystallin or when it interacted with its natural binding partners in milk, αS- and β-casein. Likewise, incubating Aβ1–40 with αB-crystallin inhibited both Aβ1–40 fibril formation and the associated cell toxicity. Importantly, by inhibiting fibril formation, αB-crystallin prevents the
cell toxicity associated with protein misfolding. 相似文献
7.
Caraci F Spampinato S Sortino MA Bosco P Battaglia G Bruno V Drago F Nicoletti F Copani A 《Cell and tissue research》2012,347(1):291-301
Alzheimer’s disease (AD) is a neurodegenerative disorder that affects about 35 million people worldwide. Current drugs for
AD only treat the symptoms and do not interfere with the underlying pathogenic mechanisms of the disease. AD is characterized
by the presence of β-amyloid (Aβ) plaques, neurofibrillary tangles, and neuronal loss. Identification of the molecular determinants
underlying Aβ-induced neurodegeneration is an essential step for the development of disease-modifying drugs. Recently, an
impairment of the transforming growth factor-β1 (TGF-β1) signaling pathway has been demonstrated to be specific to the AD
brain and, particularly, to the early phase of the disease. TGF-β1 is a neurotrophic factor responsible for the initiation
and maintenance of neuronal differentiation and synaptic plasticity. The deficiency of TGF-β1 signaling is associated with
Aβ pathology and neurofibrillary tangle formation in AD animal models. Reduced TGF-β1 signaling seems to contribute both to
microglial activation and to ectopic cell-cycle re-activation in neurons, two events that contribute to neurodegeneration
in the AD brain. The neuroprotective features of TGF-β1 indicate the advantage of rescuing TGF-β1 signaling as a means to
slow down the neurodegenerative process in AD. 相似文献
8.
Feda E. Ali Kevin J. Barnham Colin J. Barrow Frances Separovic 《International journal of peptide research and therapeutics》2003,10(5-6):405-412
Summary Metal-catalyzed oxidation (MCO) can lead to damage of bio-molecules and is implicated in neurodegenerative diseases, such
as Alzheimer's disease (AD). The amino acid residues, tyrosine, histidine and methionine, have been proposed to play important
roles in metal mediated oxidative stress and subsequent reactions of amyloid β peptide (Aβ) a major contributor in the pathogenesis
of AD. The MCO of Aβ residues, particularly histidine, methionine and tyrosine, and reviewed. MCO of Aβ histidine and tyrosine
residues can facilitate oligomerization and may play a role in both amyloid formation and Aβ neurotoxicity. Further work is
needed to determine the importance of Aβ oxidation in AD and the role of Aβ oxidation products and oxidative stress in disease
progression. The mechanisms of Aβ MCO are complex and multiple reaction products can form. Further study is needed to determine
the mechanisms by which Aβ MCO occursin vivo. In addition, new analytical methods are required to monitor the formation of Aβ MCO products formed during AD. The copper-H2O2 redox system provides a chemical model by which Aβ MCO can be studiedin vitro and can be used to produce oxidatively modified amino acid residues for use as standards in developing new analytical methods
to monitor Aβ MCO. 相似文献
9.
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
10.
Previous studies have shown that β-amyloid (Aβ) peptides are neurotoxic. Recent data suggest that neurons undergoing Aβ-induced
cell death exhibit characteristics that correspond to the classical features of apoptosis, suggesting that these cells may
initiate a program of cell death. This chapter explores the criteria and precautions that must be applied to evaluate mechanisms
of cell death in vitro and in vivo, discusses the evidence supporting an apoptotic mechanism of cell death in response to
Aβ in cultured neurons, and describes potential correlations for these findings in the Alzheimer's disease brain. In addition,
cellular signaling pathways that may be associated with apoptosis in response to Aβ are examined, and support for apoptosis
as a mechanism of cell death for other neurodegeneration-inducing stimuli (e.g., oxidative injury) is described. The connection
of multiple stimuli that induce neuronal cell death to an apoptotic mechanism suggests that apoptosis could play a central
role in neurodegeneration in the brain. 相似文献
11.
The pathological hallmarks of Alzheimer’s disease (AD) include formation of extracellular amyloid-β peptide (Aβ) and inflammatory
responses. Numerous studies have reported that cerebral microvascular Aβ deposition promotes neuroinflammation in AD. Matrix
metalloproteinases (MMPs) are involved in the cleavage of extracellular matrix proteins and regulation of growth factors,
receptors, and adhesion molecules. Relatively little is known about the involvement of MMPs as inflammatory mediators in the
pathological processes of AD. In this study, we explored the signaling pathway of MMP-2 up-regulation by Aβ in brain endothelial
cells (BECs) of mice. Using Western blots, we found that inhibitors of extracellular-signal-regulated kinases (ERK) and c-Jun
N-terminal kinase (JNK) significantly decreased Aβ-induced MMP-2 expression in BECs. Furthermore, antibody neutralization
of the receptor for advanced glycation endproducts effectively blocked Aβ-induced activation of ERK and JNK and their contribution
to elevated MMP-2 expression in BECs. Our results suggest that increased MMP-2 expression induced by the interaction of Aβ
with RAGE in BECs may contribute to enhanced vascular inflammatory stress in Aβ-related vascular disorders, such as cerebral
amyloid angiopathy and AD. This study offers new insights into neuroinflammation in the progression of AD. 相似文献
12.
A progressive accumulation of amyloid β-protein (Aβ) is widely recognized as a pathological hallmark of Alzheimer’s disease
(AD). Substantial progress has been made toward understanding the neurodegenerative cascade initiated by small soluble species
of Aβ and recent evidence supports the notion that microtubule rearrangements may be proximate to neuritic degeneration and
deficits in episodic declarative memory. Here, we examined primary cortical neurons for changes in markers associated with
synaptic function following exposure to sublethal concentrations of non-aggregated Aβ-peptide. This data show that soluble
Aβ species at a sublethal concentration induce degradation of the microtubule-associated protein 1A (MAP1A) without concurrently
affecting dendritic marker MAP2 and/or the pre-synaptic marker synaptophysin. In addition, MAP1A was found to highly co-localize
with the postsynaptic density-95 (PSD-95) protein, proposing that microtubule perturbations might be central for the Aβ-induced
neuronal dysfunctions as PSD-95 plays a key role in synaptic plasticity. In conclusion, this study suggests that disruption
of MAP1A could be a very early manifestation of Aβ-mediated synaptic dysfunction—one that presages the clinical onset of AD
by years. Moreover, our data support the notion of microtubule-stabilizing agents as effective AD drugs. 相似文献
13.
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
14.
Giovanna Cenini Cristina Cecchi Anna Pensalfini Sara Anna Bonini Giulia Ferrari-Toninelli Gianfranco Liguri Maurizio Memo Daniela Uberti 《Amino acids》2010,38(4):1107-1106
A neuropathological characteristic of Alzheimer’s disease is the extracellular accumulation of amyloid beta peptide (Aβ) in
neuritic plaques. Recent evidences suggested that soluble Aβ oligomers are the predominant neurotoxic species for neurons.
Thus, considerable attention has been paid to discriminate the cytotoxic pathways of Aβ pre-fibrillar aggregates and mature
fibrils. We showed that the mechanisms by which Aβ oligomers and fibrils generated reactive oxygen species differ in terms
of site of production and kinetics, suggesting the involvement of different intra/extracellular pathways. 相似文献
15.
Amyloid-beta peptide (Aβ) is known to induce the redox imbalance, mitochondrial dysfunction and caspase activation, resulting
in neuronal cell death. Treatment with antioxidants provided a new therapeutic strategy for Alzheimer’s disease (AD) patients.
Here we investigate the effects of purple sweet potato anthocyanins (PSPA), the known strong free radical scavengers, on Aβ
toxicity in PC12 cells. The results showed that pretreatment of PC12 cells with PSPA reduced Aβ-induced toxicity, intracellular
reactive oxygen species (ROS) generation and lipid peroxidation dose-dependently. In parallel, cell apoptosis triggered by
Aβ characterized with the DNA fragmentation and caspase-3 activity were also inhibited by PSPA. The concentration of intracellular
Ca2+ and membrane potential loss associated with cell apoptosis were attenuated by PSPA. These results suggested that PSPA could
protect the PC-12 cell from Aβ-induced injury through the inhibition of oxidative damage, intracellular calcium influx, mitochondria
dysfunction and ultimately inhibition of cell apoptosis. The present study indicates that PSPA may be a promising approach
for the treatment of AD and other oxidative-stress-related neurodegenerative diseases. 相似文献
16.
Hani Atamna 《Journal of bioenergetics and biomembranes》2009,41(5):457-464
Soluble oligomers and/or aggregates of Amyloid-β (Aβ) are viewed by many as the principal cause for neurodegeneration in Alzheimer’s
disease (AD). However, the mechanism by which Aβ and its aggregates cause neurodegeneration is not clear. The toxicity of
Aβ has been attributed to its hydrophobicity. However, many specific mitochondrial cytopathologies e.g., loss of complex IV,
loss of iron homeostasis, or oxidative damage cannot be explained by Aβ’s hydrophobicity. In order to understand the role
of Aβ in these cytopathologies we hypothesized that Aβ impairs specific metabolic pathways. We focused on heme metabolism
because it links iron, mitochondria, and Aβ. We generated experimental evidence showing that Aβ alters heme metabolism in
neuronal cells. Furthermore, we demonstrated that Aβ binds to and depletes intracellular regulatory heme (forming an Aβ-heme
complex), which provides a strong molecular connection between Aβ and heme metabolism. We showed that heme depletion leads
to key cytopathologies identical to those seen in AD including loss of iron homeostasis and loss of mitochondrial complex
IV. Aβ-heme exhibits a peroxidase-like catalytic activity, which catalytically accelerates oxidative damage. Interestingly,
the amino acids sequence of rodent Aβ (roAβ) and human Aβ (huAβ) is identical except for three amino acids within the hydrophilic
region, which is also the heme-binding motif that we identified. We found that huAβ, unlike roAβ, binds heme tightly and forms
a peroxidase. Although, roAβ and huAβ equally form fibrils and aggregates, rodents do not develop AD-like neuropathology.
These findings led us to propose a new mechanism for mitochondrial dysfunction and huAβ’s neurotoxicity. This mechanism prompted
the development of methylene blue (MB), which increased heme synthesis, complex IV, and mitochondrial function. Thus, MB may
delay the onset and progression of AD and serve as a lead to develop novel drugs to treat AD. 相似文献
17.
Overload of intracellular Ca2+ has been implicated in the pathogenesis of neuronal disorders, such as Alzheimer’s disease. Various mechanisms produce abnormalities
in intracellular Ca2+ homeostasis systems. L-type Ca2+ channels have been known to be closely involved in the mechanisms underlying the neurodegenerative properties of amyloid-β
(Aβ) peptides. However, most studies of L-type Ca2+ channels in Aβ-related mechanisms have been limited to CaV1.2, and surprisingly little is known about the involvement of CaV1.3 in Aβ-induced neuronal toxicity. In the present study, we examined the expression patterns of CaV1.3 after Aβ25–35 exposure for 24 h and compared them with the expression patterns of CaV1.2. The expression levels of CaV1.3 were not significantly changed by Aβ25–35 at both the mRNA levels and the total protein level in cultured hippocampal neurons. However, surface protein levels of CaV1.3 were significantly increased by Aβ25–35, but not by Aβ35–25. We next found that acute treatment with Aβ25–35 increased CaV1.3 channel activities in HEK293 cells using whole-cell patch-clamp recordings. Furthermore, using GTP pulldown and co-immunoprecipitation
assays in HEK293 cell lysates, we found that amyloid precursor protein interacts with β3 subunits of Ca2+ channels instead of CaV1.2 or CaV1.3 α1 subunits. These results show that Aβ25–35 chronically or acutely upregulates CaV1.3 in the rat hippocampal and human kidney cells (HEK293). This suggests that CaV1.3 has a potential role along with CaV1.2 in the pathogenesis of Alzheimer’s disease. 相似文献
18.
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
19.
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
20.
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