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1.
Alzheimer’s disease (AD) is characterized by excessive cerebrovascular deposition of the β-amyloid peptide (Aβ). The investigation
of Aβ transport across the blood-brain barrier (BBB) has been hindered by inherent limitations in the cellular systems currently
used to model the BBB, such as insufficient barrier properties and poor reproducibility. In addition, many of the existing
models are not of human or brain origin and are often arduous to establish and maintain. Thus, we characterized an in vitro
model of the BBB employing human brain microvascular endothelial cells (HBMEC) and evaluated its utility to investigate Aβ
exchange at the blood-brain interface. Our HBMEC model offers an ease of culture compared with primary isolated or coculture
BBB models and is more representative of the human brain endothelium than many of the cell lines currently used to study the
BBB. In our studies, the HBMEC model exhibited barrier properties comparable to existing BBB models as evidenced by the restricted
permeability of a known paracellular marker. In addition, using a simple and rapid fluormetric assay, we showed that antagonism
of key Aβ transport proteins significantly altered the bi-directional transcytosis of fluorescein-Aβ (1–42) across the HBMEC
model. Moreover, the magnitude of these effects was consistent with reports in the literature using the same ligands in existing
in vitro models of the BBB. These studies establish the HBMEC as a representative in vitro model of the BBB and offer a rapid
fluorometric method of assessing Aβ exchange between the periphery and the brain. 相似文献
2.
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
3.
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
4.
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
5.
Lambracht-Washington D Qu BX Fu M Anderson LD Stüve O Eagar TN Rosenberg RN 《Cellular and molecular neurobiology》2011,31(6):867-874
The pathogenesis of Alzheimer’s disease (AD) has been strongly associated with the accumulation of amyloid beta (Aβ) peptides
in brain, and immunotherapy targeting Aβ provides potential for AD prevention. A clinical trial in which AD patients were
immunized with Aβ42 peptide was stopped when 6% of participants showed meningoencephalitis, apparently due to an inflammatory
Th1 immune response. Previously, we and other have shown that Aβ42 DNA vaccination via gene gun generates a Th2 cellular immune
response, which was shown by analyses of the respective antibody isotype profiles. We also determined that in vitro T cell
proliferation in response to Aβ42 peptide re-stimulation was absent in DNA Aβ42 trimer-immunized mice when compared to Aβ42
peptide-immunized mice. To further characterize this observation prospectively and longitudinally, we analyzed the immune
response in wild-type mice after vaccination with Aβ42 trimer DNA and Aβ42 peptide with Quil A adjuvant. Wild-type mice were
immunized with short-term (1–3× vaccinations) or long-term (6× vacinations) immunization strategies. Antibody titers and isotype
profiles of the Aβ42 specific antibodies, as well as cytokine profiles and cell proliferation studies from this longitudinal
study were determined. Sufficient antibody titers to effectively reduce Aβ42, but an absent T cell proliferative response
and no IFNγ or IL-17 secretion after Aβ42 DNA trimer immunization minimizes the risk of inflammatory activities of the immune
system towards the self antigen Aβ42 in brain. Therefore, Aβ42 DNA trimer immunization has a high probability to be effective
and safe to treat patients with early AD. 相似文献
6.
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
7.
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
8.
Cai Zhiyou Yan Yong Sun Shanquan Zhang Jun Huang Liangguo Yan Ling Li Jieying 《Neurochemical research》2009,34(7):1226-1235
Chronic cerebral hypoperfusion (CCH) increases the risk of Alzheimer disease (AD) through several biologically plausible pathways,
but the relationship between CCH and the development of AD remains uncertain. To investigate expression of APP, BACE1 and
Aβ in the hippocampus of BCCAO rats and study pathophysiological mechanism of AD from CCH. CCH rat model was established by
chronic bilateral common carotid artery occlusion (BCCAO). Behavior was evaluated after BCCAO with Morris water maze and open-field
task. Expression of Aβ was measured by enzyme linked immunosorbent assay (ELISA). β-Amyloid precursor protein cleavage enzyme
1 (BACE1) and β-amyloid precursor protein (APP) were tested by ELISA, Western blotting and RT-PCR. Cognitive impairment occurred
with CCH by Morris water maze test and open-field task. The BACE1 and Aβ level in BCCAO rats was more increased than sham-operation
control rats (P < 0.01) but APP had no difference(P > 0.05). The expression of BACE1 and Aβ has no inter-grouop difference in BCCAO rats (P > 0.05). The level of BACE1 and Aβ had positive correlation with cognitive impairment (P < 0.01) while no correlation was observed between APP and cognitive impairment. Chronic cerebral ischemia contributes to
cognitive impairment and vascular pathogenesis of Alzheimer’s disease that chronic cerebral hypoperfusion increases BACE1
and Aβ level in brain. 相似文献
9.
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
10.
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
11.
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
12.
David H. Small Lisa R. Fodero Dusan Losic Cindy Chu Marie-Isabel Aguilar Lisandra L. Martin Mary Chebib 《International journal of peptide research and therapeutics》2003,10(5-6):401-404
Alzheimer's disease (AD) is caused by the accumulation of β-amyloid protein (Aβ) in the brain. The aggregation of β-amyloid
protein to higher molecular weight fibrillar forms is also considered to be an important step in the pathogenesis of the disease.
The memory problems associated with AD are likely to be caused by changes in synaptic plasticity. Recent studies suggest that
Aβ binds to the α 7 nicotinic acetylcholine receptor (α 7 nAChR), which plays an important role in synaptic plasticity and
memory. A loop domain localized towards the C-terminus of the extracellular region of the receptor has been identified as
forming part of a putative Aβ-binding site. In cell culture experiments, the binding of Aβ to the α 7 nAChR has been found
to cause an increase in the level of acetylcholinesterase, which is also increased around amyloid plaques in the AD brain.
These studies indicate that the Aβ-binding site on the α 7 nAChR receptor is an important new target for therapeutic development
in AD. 相似文献
13.
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
14.
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
15.
Yuan C Yi L Yang Z Deng Q Huang Y Li H Gao Z 《Journal of biological inorganic chemistry》2012,17(2):197-207
Amyloid beta (Aβ) peptide accumulation has been demonstrated to play a central role in Alzheimer’s disease (AD). Substantial
evidence indicates that protein nitrotyrosination contributes to Aβ-dependent neurotoxicity; however, the molecular mechanism
is unknown. Recent research has shown that Aβ complexes with heme to form Aβ–heme, and increases the pseudo-peroxidase activity
of heme. We found that Aβ–heme uses H2O2 and NO2
− to cause nitration of enolase and synaptic proteins more effectively than heme. Thus, the increased peroxidase activity of
Aβ–heme may be the molecular link between excess Aβ and the widespread protein nitration in AD. Interestingly, the site of
enolase nitration that was catalyzed by Aβ–heme is different from that induced by heme. Moreover, the secondary structural
perturbations of Aβ–heme-treated and heme-treated enolase are also different. These observations suggest that Aβ–heme targets
specific amino acid sequences in enolase. Furthermore, our data show that Aβ–heme peroxidase activity is independent of the
aggregation state of Aβ, suggesting an important role of soluble Aβ in addition to Aβ aggregates and oligomers in AD pathogenesis. 相似文献
16.
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
17.
Alzheimer’s disease (AD) is characterized by the depositions of amyloid-β (Aβ) proteins, resulting in a reduction of choline
acetyltransferase (ChAT) activity of AD brain in the early stages of the disease. Several growth factors, including brain-derived
neurotrophic factor (BDNF), insulin-like growth factor (IGF)-1 and glial cell-derived neurotrophic factor (GDNF) are known
to protect neuronal cell death in several neurodegenerative both in vitro and in vivo models. In this study, septal neurons
were prepared from septal nucleus of embryonic (day 16-17) rat brain and treated with monomeric, oligomeric or fibrillar Aβ1-42 peptide. Oligomeric Aβ1-42, (10 μM) was the most potent at sublethal dose. Septal neuron cultures treated with BDNF, IGF-1 or GDNF or co-cultured with
genetically modified human neural progenitor cells (hNPCs) secreting these neurotrophic factors (but not allowing contact
between the two cell types), were protected from oligomeric Aβ1-42 peptide-induced cell death, and these trophic factors enhanced cholinergic functions by increasing ChAT expression level.
These results indicate the potential of employing transplanted hNPCs for treatment of AD. 相似文献
18.
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
19.
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
20.
Thapak Pavan Khare Pragyanshu Bishnoi Mahendra Sharma Shyam Sunder 《Cellular and molecular neurobiology》2022,42(4):1211-1223
Cellular and Molecular Neurobiology - β-Amyloid (Aβ) peptide is a characteristic feature of Alzheimer’s disease (AD) and accumulation of Aβ is associated with loss of synaptic... 相似文献