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1.
Luchsinger JA Tang MX Miller J Green R Mehta PD Mayeux R 《Neurochemical research》2007,32(4-5):775-781
Background Elevated plasma homocysteine and amyloid β (Aβ) have been associated with Alzheimer’s disease (AD). We investigated the cross-sectional
association between these biomarkers.
Methods We used linear regression to relate plasma homocysteine and Aβ adjusting for age, gender, creatinine, APOE-ε4, and ethnic
group in 327 persons aged 78 ± 6.6 years.
Results Plasma homocysteine correlated with age, serum creatinine, plasma Aβ40 and Aβ42, and was inversely correlated with serum vitamin
B12, and folate. Aβ42, but not Aβ40, was related to later development of dementia. Homocysteine was related to higher Aβ40
levels (coefficient = 2.0; P < 0.0001) and this association was attenuated after adjustment for creatinine (coefficient = 1.0; P < 0.0001). The crude association between homocysteine and Aβ42 was weaker (coefficient = 0.5; P = 0.01) and became non-significant after adjustment for creatinine (coefficient = 0.4; P = 0.06). These associations were unrelated to ethnicity, the presence of APOE-ε4 or dementia. Analyses by quartiles of homocysteine
showed that these association were driven primarily by the fourth quartile.
Conclusions Plasma homocysteine is directly related to Aβ40. The association with Aβ42 is not significant. These results seem to indicate
that homocysteine is related to aging but not specifically to AD.
Special issue dedicated to John P. Blass. 相似文献
2.
A<Emphasis Type="Bold">β</Emphasis> Upregulates and Colocalizes with LGI3 in Cultured Rat Astrocytes
Kimura N Ishii Y Suzaki S Negishi T Kyuwa S Yoshikawa Y 《Cellular and molecular neurobiology》2007,27(3):335-350
1. The leucine-rich glioma inactivated (LGI) family of genes encodes a leucine-rich repeat (LRR) protein, proteins that are
thought to be specifically involved in protein–protein and protein–matrix interactions. Since amyloid beta peptide (Aβ) has
been previously shown to induce the expression of another LRR-encoding gene in neural cells, we assessed how Aβ affects LGI
gene expression in rat primary cerebral cortical cultures and astrocyte cultures. Both RT-PCR and Western Blotting analyses
revealed that Aβ robustly induced the expression of LGI3 in rat astrocyte cultures.
2. Western Blotting analyses also showed that both glial fibrillary acidic protein (GFAP) and apolipoprotein E (ApoE) significantly
increased coincidentally with the Aβ-induced upregulation of LGI3. Immunocytochemistry showed that LGI3 colocalized with Aβ
at plasma membranes and also with internalized Aβ in astrocytes. These findings suggest that activated LGI3 may be involved
in the astroglial response against Aβ. 相似文献
3.
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
4.
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
5.
Neprilysin Deficiency-Dependent Impairment of Cognitive Functions in a Mouse Model of Amyloidosis 总被引:1,自引:0,他引:1
Alzheimer’s disease, responsible for the vast majority of dementia cases in the elderly population, is caused by accumulation
of toxic levels of amyloid β peptide (Aβ) in the brain. Neprilysin is a major enzyme responsible for the degradation of Aβ in vivo. We have previously
shown that elevation of neprilysin levels in the brain delays the deposition of Aβ -plaques in a mouse model of amyloidosis
and that lack of neprilysin leads to increased Aβ generation and to signs of incipient neurodegeneration in mouse brains.
This study was designed to test whether low brain levels of neprilysin affect the amyloid pathology or perturb the learning
and memory performance of mice. Double-mutated mice carrying a targeted depletion of one allele of Mme, the gene encoding neprilysin, and over-expressing human amyloid precursor protein (APP), exhibited a reinforced amyloid
pathology in comparison with their APP transgenic littermates. Moreover, in contrast to their parental lines, these mice were
impaired in the Morris water maze learning and memory paradigm and showed facilitated extinction in the conditioned taste
aversion test. These data suggest that even a partial neprilysin deficiency, as is found during aging, exacerbates amyloid
pathology and may impair cognitive functions.
Special issue to Honor Dr. Akitane Mori. 相似文献
6.
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
7.
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
8.
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
9.
Feda E. Ali Frances Separovic Colin J. Barrow Shenggen Yao Kevin J. Barnham 《International journal of peptide research and therapeutics》2006,12(2):153-164
The accumulation of senile plaques composed primarily of aggregated amyloid β-peptide (Aβ), is the major characteristic of Alzheimer’s disease. Many studies correlate plaque accumulation and the presence of metal ions, particularly copper and zinc. The metal binding sites of the amyloid Aβ peptide of Alzheimer’s disease are located in the N-terminal region of the full-length peptide. In this work, the interactions with metals of a model peptide comprising the first 16 amino acid residues of the amyloid Aβ peptide, Aβ(1–16), were studied. The effect of Cu2+ and Zn2+ binding to Aβ(1–16) on peptide structure and oligomerisation are reported. The results of ESI-MS, gel filtration chromatography and NMR spectroscopy demonstrated formation of oligomeric complexes of the peptide in the presence of the metal ions and revealed the stoichiometry of Cu2+ and Zn2+ binding to Aβ(1–16), with Cu2+ showing a higher affinity for binding the peptide than Zn2+. 相似文献
10.
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
11.
Céline Rivière Jean-Claude Delaunay Françoise Immel Christophe Cullin Jean-Pierre Monti 《Neurochemical research》2009,34(6):1120-1128
Alzheimer’s disease (AD) is characterized by deposits of amyloid in various tissues. The neuronal cytotoxicity of Aβ peptides
is attributed not only to various mechanisms but also to amyloid fibrils and soluble oligomeric intermediates. Consequently,
finding molecules to prevent or reverse the oligomerization and fibrillization of Aβ could be of therapeutic value in the
treatment of AD. We show that piceid, a polyphenol of the stilbene family, destabilized fibrils and oligomers to give back
monomers that are not neurotoxic molecules. The mechanism of this destabilization could be a dynamic interaction between the
polyphenol and the Aβ that could open the hydrophobic zipper and shift the reversible equilibrium “random coil⇔β-sheet” to
the disordered structure. 相似文献
12.
Bilobalide (BB), a sesquiterpenoid extract of Ginkgo biloba leaves, has been demonstrated to have neuroprotective effects. The neuroprotective mechanisms were suggested to be associated
with modulation of intracellular signaling cascades such as the phosphatidyl inositol 3-kinase (PI3K) pathway. Since some
members of intracellular signalling pathways such as PI3K have been demonstrated to be involved in amyloid precursor protein
(APP) processing, the present study investigated whether BB has an influence on the β-secretase-mediated APP cleavage via
PI3K-dependent pathway. Using HT22 cells and SAMP8 mice (a senescence-accelerated strain of mice), this study showed that
BB treatment reduced generation of two β-secretase cleavage products of APP, the amyloid β-peptide (Aβ) and soluble APPβ (sAPPβ),
via PI3K-dependent pathway. Additionally, glycogen synthase kinase 3β (GSK3β) signaling might be involved in BB-induced Aβ
reduction as a downstream target of the activated PI3K pathway. BB showed no significant effects on β-site APP cleaving enzyme
1 (BACE-1) or γ-secretase but inhibited the β-secretase activity of another protease cathepsin B, suggesting that BB-induced
Aβ reduction was probably mediated through modulation of cathepsin B rather than BACE-1. Similarly, inhibition of GSK3β did
not affect BACE-1 activity but decreased cathepsin B activity, suggesting that the PI3K-GSK3β pathway was probably involved
in BB-induced Aβ reduction. Increasing evidence suggests that decreasing Aβ production in the brain via modulation of APP
metabolism should be beneficial for the prevention and treatment of Alzheimer’s disease (AD). BB may offer such an approach
to combat AD. 相似文献
13.
Accumulating evidence suggests that the conversion of Aβ peptides to soluble, neurotoxic polymers is the key event in the
development of Alzheimer’s disease (AD). Moreover, interactions between Aβ peptides and neuronal membrane lipids likely play
a vital role in developing the neurotoxicity associated with AD. The aim of this study is to assess whether lipid matrix of
neuronal membranes is affected by the accumulation of Aβ peptides in double transgenic mouse model of AD expressing both mutant
human β-amyloid precursor protein (APP) and presenilin 1 (PS1). We apply high pressure liquid chromatography with an evaporative
light scattering detector to compare levels of cholesterol, galactocerebrosides, and phospholipid subclasses simultaneously in cortex samples between AD double transgenic mice at 4 months of age when Aβ production and amyloid plaque deposition is
just beginning and at 9 months, when there is advanced Aβ levels and plaque deposition compared to age-matched wild-type (B6/SJL)
mice. Both cholesterol (CL) and phospholipids (PL) are significantly lower in 9-month-old AD mice than the same age of B6/SJL
mice. Among PL subclasses, phosphatidylethanolamine (PE), phosphatidylserine (PS) and phosphatidylcholine (PC) are selectively
reduced in 9-month-old AD mice. The molar ratios of CL to PL in 9-month-old AD mice (1.19 ± 0.27) were significantly higher
than those of 9-month-old B6/SJL mice (0.81 ± 0.08). In keeping with decreased levels of PL, there are also significant reductions
of very long-chain n-3 fatty acids (docosahexaenoic acid) and n-6 fatty acid (arachidonic acid) in 9-month-old AD mice. On
the other hand, ratios of total n-6 to total n-3 fatty acids were significantly higher in 9-month-old AD mice than in the
same age of B6/SJL mice. Taken together, our present data support a role for the interactions of amyloid-β peptide and neuronal
membranes in the subsequent development of AD.
Special issue article in honor of Dr. George DeVries. 相似文献
14.
Dergunov AD 《Biochemistry. Biokhimii?a》2006,71(7):707-712
Three isoforms of human plasma apolipoprotein E (apoE) are ligands to lipoprotein receptors and influence in different manner
the synthesis and catabolism of pro-atherogenic triglyceride-rich lipoproteins. Among three isoforms, the apoE4 isoform is
associated with increased frequency of atherosclerosis and Alzheimer’s disease (AD). The conformational transitions of β-amyloid
(Aβ) influenced by apoE and serum amyloid P (SAP) component are key events in AD development, the accumulation of intermediate
diffusible and soluble oligomers of Aβ being of particular significance. SAP and apoE, in a different manner for the three
isoforms, serve as “pathological” chaperones during the aggregation of Aβ considered as a conformation-prone process. In turn,
apoE consisting of two domains self-associates in solution and intermediate structures differently populated for the three
isoforms exist. The different structures of the three isoforms determine their different distribution among various plasma
lipoproteins. The structural and metabolic consideration of the common apoE pathway(s) in two pathologies assumes four molecular
targets for AD correction: (i) inhibition of the accumulation of diffusible soluble Aβ oligomers; (ii) inhibition of apoE
synthesis and secretion by astrocytes, in particular, under lipid-lowering therapy; (iii) inhibition of the binding of apoE
and/or SAP to Aβ; (iv) stimulation of the expression of cholesterol transporter ABCA1.
Published in Russian in Biokhimiya, 2006, Vol. 71, No. 7, pp. 876–881. 相似文献
15.
Niklas Mattsson Daniel Bremell Rolf Anckarsäter Kaj Blennow Henrik Anckarsäter Henrik Zetterberg Lars Hagberg 《BMC neurology》2010,10(1):51
Background
The metabolism of amyloid precursor protein (APP) and β-amyloid (Aβ) is widely studied in Alzheimer's disease, where Aβ deposition and plaque development are essential components of the pathogenesis. However, the physiological role of amyloid in the adult nervous system remains largely unknown. We have previously found altered cerebral amyloid metabolism in other neuroinflammatory conditions. To further elucidate this, we investigated amyloid metabolism in patients with Lyme neuroborreliosis (LNB). 相似文献16.
Christine Talmard Rodrigue Leuma Yona Peter Faller 《Journal of biological inorganic chemistry》2009,14(3):449-455
The amyloidoses are a group of disorders characterized by aberrant protein folding and assembly, leading to the deposition
of insoluble protein fibrils (amyloid), which provokes cell dysfunction and later cell death. One of the physiologically relevant
environmental factors able to affect the conformation and hence the aggregation properties of amyloidogenic proteins/peptides
is metal ions. Zn(II) promotes aggregation of most amyloidogenic peptides/proteins in vitro, including amyloid β protein (Aβ),
but the underlying mechanism is not known. To better understand this mechanism the present study focused on the partially
α-helical conformer, supposed to be an intermediate in Aβ aggregation. This partially α-helical conformer is stabilized by
10–20% 2,2,2-trifluoroethanol (TFE): therefore, the influence of Zn binding on the aggregation of the amylidogenic model peptide
Aβ(1–28) (Aβ28) was investigated at different TFE concentrations. The results showed a synergistic effect of Zn(II) and 10%
TFE, i.e., that either Zn or 10% TFE accelerated Aβ28 aggregation on its own, but with them together an at least 10 times
promotion of Aβ28 aggregation was observed. Further studies by thioflavin T fluorescence spectroscopy, transmission electron
microscopy, and circular dichroism (CD) spectroscopy suggested that the aggregates of Zn-Aβ28 formed in 10%TFE contain a β-sheet
secondary structure and are more of the amyloid type. CD spectroscopy indicated that Zn binding disrupted partially the α-helical
structure of Aβ28 in TFE. Thus, we propose that the promotion of Aβ28 aggregation by Zn is based on the transformation of
the partially α-helical conformer (intermediate) towards the β-sheet amyloid structure by a destabilization of the α-helix
in the intermediate.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.
相似文献
Peter FallerEmail: Email: |
17.
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
18.
Christa J. Maynard Roberto Cappai Irene Volitakis Katrina M. Laughton Colin L. Masters Ashley I. Bush Qiao-Xin Li 《Cellular and molecular neurobiology》2009,29(5):757-767
Aberrant metal homeostasis may enhance the formation of reactive oxygen species and Aβ oligomerization and may therefore be
a contributing factor in Alzheimer’s disease. This study investigated the effect of chronic high intake of dietary Zn or Cu
on brain metal levels and the accumulation and solubility of Aβ in vivo, using a transgenic mouse model that over expresses
the C-terminal containing Aβ fragment of human amyloid precursor protein but does not develop amyloid deposits. Exposure to
chronic high Zn or Cu in the drinking water resulted in only slight elevations of the respective metals in the brain. Total
Aβ levels were unchanged although soluble Aβ levels were slightly decreased, without visible plaque formation, enhanced gliosis,
antioxidant upregulation or neuronal loss. This study indicates that brain metal levels are only marginally altered by long
term oral exposure to extremely high Cu or Zn levels, and that this does not induce Aβ-amyloid formation in human Aβ expressing,
amyloid-free mice, although this is sufficient to modulate Aβ solubility in vivo. 相似文献
19.
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
20.
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