共查询到20条相似文献,搜索用时 31 毫秒
1.
A. Fisher R. Brandeis S. Chapman Z. Pittel D. M. Michaelson 《Journal of neurochemistry》1998,70(5):1991-1997
Abstract: Recent studies suggest that apolipoprotein E (apoE) plays a specific role in brain cholinergic function and that the E4 allele of apoE (apoE4), a major risk factor for Alzheimer's disease (AD), may predict the extent of cholinergic dysfunction and the efficacy of cholinergic therapy in this disease. Animal model studies relevant to this hypothesis revealed that apoE-deficient (knockout) mice have working memory impairments that are associated with distinct dysfunction of basal forebrain cholinergic neurons. Cholinergic replacement therapy utilizing M1 -selective muscarinic agonists has been proposed as effective treatment for AD patients. In the present study, we examined whether the memory deficits and brain cholinergic deficiency of apoE-deficient mice can be ameliorated by the M1 -selective agonist 1-methylpiperidine-4-spiro-(2'-methylthiazoline), [AF150(S)]. Treatment of apoE-deficient mice with AF150(S) for 3 weeks completely abolished their working memory impairments. Furthermore, this reversal of cognitive deficit was associated with a parallel increase of histochemically determined brain choline acetyltransferase and acetylcholinesterase levels and with the recovery of these cholinergic markers back to control levels. These findings show that apoE deficiency-related cognitive and cholinergic deficits can be ameliorated by M1 -selective muscarinic treatment. They also provide a novel model system for development and evaluation of therapeutic strategies directed specifically at the AD patients whose condition is attributed to the apoE genotype. 相似文献
2.
The review collects the emerging information about zinc transporter 3 (ZnT3). ZnT3 has been associated with Alzheimer’s disease,
airway diseases and diabetes. ZnT3 was discovered and cloned in 1996. Since then, the major interest in the protein has been
in its ability to transport zinc into pre-synaptic vesicles of glutamatergic neurones and its role during the development
of amyloid β plaques in Alzheimer’s disease. Increasing evidence suggests that ZnT3 is present in various cell types like
different cell types in the brain, cells from adipose tissue, beta-cells from pancreatic islets, epithelial cells, cells from
testis, prostate cancer cells and cells from retina. The expression of ZnT3 is regulated by age, hormones, fatty acids, zinc
chelation, and glucose. 相似文献
3.
P. Eikelenboom J. M. Rozemuller G. Kraal F. C. Stam P. A. McBride M. E. Bruce H. Fraser 《Virchows Archiv. B, Cell pathology including molecular pathology》1991,60(1):329-336
Complement proteins of the classical pathway can be immunohistochemically identified in cerebral amyloid plaques in Alzheimer’s
disease. Microglial cells in and around amyloid plaques express class II major histocompatibility (MHC) antigens and complement
receptors CR3 and CR4. Negative immunostaining for immunoglobulins and for T-cell subsets in the brain parenchyma demonstrates
a lack of evidence for the involvement of specific immune responses (such as an immune complex-mediated complement activation
or a cell-mediated immune response) in cerebral amyloid deposits in Alzheimer’s disease. Cerebral amyloid plaques in scrapie-affected
mice (slow-virus induced encephalopathy) do not contain complement factors C1q and C3c and are not clustered with microglial
cells expressing MHC class II molecules or complement receptor CR3. The data presented suggest the induction of a reactive
inflammatory process by β/A4 amyloid in the human brain, but not by scrapie-induced PrP amyloid in mice. Our findings do not
support the hypothesis that the immune system is involved in the generation of amyloid plaques in Alzheimer’s disease.
This study was partly supported by a grant from the Praeventiefonds, project 28–1945 相似文献
4.
Summary. Protein misfolding and aberrant polymerization are salient features of virtually all central neurodegenerative disorders,
including Alzheimer's disease (AD), Parkinson's disease, triplet repeat disorders, tauopathies, and prion diseases. In many
instances, a single amino acid change can predispose to disease by increasing the production and/or changing the biophysical
properties of a specific protein. Possible pathogenic similarities among the cerebral proteopathies suggest that therapeutic
agents interfering with the proteopathic cascade might be effective against a wide range of diseases. However, testing compounds
preclinically will require disease-relevant animal models. Numerous transgenic mouse models of β-amyloidosis, tauopathy, and other aspects of AD have now been produced, but none of the existing models fully recapitulates
the pathology of AD. In an attempt to more faithfully replicate the human disease, we infused dilute AD-brain extracts into
Tg2576 mice at 3-months of age (i.e. 5–6 months prior to the usual onset of β-amyloid deposition). We found that intracerebral infusion of AD brain extracts results in: 1) Premature deposition of β-amyloid in eight month-old, β-amyloid precursor protein (βAPP)-transgenic mice (Kane et al., 2000); 2) augmented amyloid load in the injected hemisphere of 15 month-old transgenic
mice; 3) evidence for the spread of pathology to other brain areas, possibly by neuronal transport mechanisms; and 4) tau
hyperphosphorylation (but not neurofibrillary pathology) in axons passing through the injection site. The seeding of β-amyloid in vivo by AD brain extracts suggests pathogenic similarities between β-amyloidoses such as AD and other cerebral proteopathies such as the prionoses, and could provide a new model for studying
the proteopathic cascade and its neuronal consequences in neurodegenerative diseases.
Received June 28, 2001 Accepted August 6, 2001 Published online June 26, 2002 相似文献
5.
Vatassery GT Quach HT Smith WE Santacruz KS Roy S 《Biochimica et biophysica acta》2007,1772(7):797-803
The incorporation of radioactive alpha tocopherol by various brain regions of wild type and apolipoprotein E (apoE)-deficient mice was investigated. Labeled tocopherol was injected into the lateral cerebral ventricles of 11 weeks old, male mice. Radioactive cholesterol injected simultaneously was used as an internal standard to account for experimental variability. Most areas of the brain of apoE-deficient mice took up less of alpha tocopherol per mg of protein than wild type animals. However, specific activity of alpha tocopherol was higher in cerebellum, pons, hypothalamus, midbrain and cerebral cortex in apoE-deficient brains than the wild type. This could be due to (a) the lower levels of alpha tocopherol in apoE-deficient brain and (b) reductions in the clearance and transport of tocopherol (possibly mediated by apoE). Tocopherol uptake by hippocampus was unusual since it was lower in apoE deficiency whether the data were expressed as specific activity or per mg of protein. Nearly all of the injected alpha tocopherol remained unchanged in the brains of both apoE-deficient and wild type animals suggesting low turnover. Overall, the current data reinforce the hypothesis that apoE is a key protein involved with the transport and/or retention of alpha tocopherol in brain. 相似文献
6.
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
7.
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8.
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
9.
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
10.
It is known that protein kinase C (PKC) activity may be one of the fundamental cellular changes associated with memory function. Apolipoprotein E (apoE) deficiency causes cholinergic deficits and memory impairment. ApoE-deficient mouse has been employed as a serviceable model for studying the relation between apoE and the memory deficit induced by cholinergic impairment. Brain-fatty acid binding protein (b-FABP) might be functional during development of the nervous system. Peroxisome proliferator-activated receptor (PPAR) is involved in the early change in lipid metabolism. We investigated the alterations not only in cerebral PKC activity, but also in the gene expressions of PKC-beta, brain-FABP and PPAR-alpha in apoE-deficient mice. The results showed that there was a lower cerebral membrane-bound PKC activity in the apoE-deficient mice than in its wild type strain (C57BL/6). But there were no significant differences in cytosolic PKC activity. PKC-beta, b-FABP and PPAR-alpha mRNA expressions in cerebrum were lowered in apoE-deficient mice. These findings may be involved in the dysfunction of the brain neurotransmission system in apoE-deficient mouse. Alternatively, these results also suggest that cerebral apoE plays an important role in brain PKC activation by maintaining an appropriate expression of b-FABP and PPAR-alpha mRNAs. 相似文献
11.
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
12.
Lack of ABCA1 considerably decreases brain ApoE level and increases amyloid deposition in APP23 mice 总被引:8,自引:0,他引:8
ABCA1 (ATP-binding cassette transporter A1) is a major regulator of cholesterol efflux and high density lipoprotein (HDL) metabolism. Mutations in human ABCA1 cause severe HDL deficiencies characterized by the virtual absence of apoA-I and HDL and prevalent atherosclerosis. Recently, it has been reported that the lack of ABCA1 causes a significant reduction of apoE protein level in the brain of ABCA1 knock-out (ABCA1-/-) mice. ApoE isoforms strongly affect Alzheimer disease (AD) pathology and risk. To determine further the effect of ABCA1 on amyloid deposition, we used APP23 transgenic mice in which the human familial Swedish AD mutant is expressed only in neurons. We demonstrated that the targeted disruption of ABCA1 increases amyloid deposition in APP23 mice, and the effect is manifested by an increased level of Abeta immunoreactivity, as well as thioflavine S-positive plaques in brain parenchyma. We found that the lack of ABCA1 also considerably increased the level of cerebral amyloid angiopathy and exacerbated cerebral amyloid angiopathy-related microhemorrhage in APP23/ABCA1-/- mice. Remarkably, the elevation in parenchymal and vascular amyloid in APP23/ABCA1-/- mice was accompanied by a dramatic decrease in the level of soluble brain apoE, although insoluble apoE was not changed. The elevation of insoluble Abeta fraction in old APP23/ABCA1-/- mice, accompanied by a lack of changes in APP processing and soluble beta-amyloid in young APP23/ABCA1-/- animals, supports the conclusion that the ABCA1 deficiency increases amyloid deposition. These results suggest that ABCA1 plays a role in the pathogenesis of parenchymal and cerebrovascular amyloid pathology and thus may be considered a therapeutic target in AD. 相似文献
13.
Cynthia L. Martel Jasmina B. Mackic Etsuro Matsubara Samuel Governale Calero Miguel Wesley Miao J. Gordon McComb Blas Frangione Jorge Ghiso Berislav V. Zlokovic 《Journal of neurochemistry》1997,69(5):1995-2004
Abstract: Cerebral capillary sequestration and blood-brain barrier (BBB) permeability to apolipoproteins E2 (apoE2), E3 (apoE3), and E4 (apoE4) and to their complexes with sAβ1–40 , a peptide homologous to the major form of soluble Alzheimer's amyloid β, were studied in perfused guinea pig brain. Cerebrovascular uptake of three apoE isoforms was low, their blood-to-brain transport undetectable, but uptake by the choroid plexus significant. Binding of all three isoforms to sAβ1–40 in vitro was similar with a K D between 11.8 and 12.9 n M . Transport into brain parenchyma and sequestration by BBB and choroid plexus were negligible for sAβ1–40 -apoE2 and sAβ1–40 -apoE3, but significant for sAβ1–40 -apoE4. After 10 min, 85% of sAβ1–40 -apoE4 taken up at the BBB remained as intact complex, whereas free sAβ1–40 was 51% degraded. Circulating apoE isoforms have contrasting effects on cerebral capillary uptake of and BBB permeability of sAβ. ApoE2 and apoE3 completely prevent cerebral capillary sequestration and blood-to-brain transport of sAβ1–40 . Conversely, apoE4, by entering brain microvessels and parenchyma as a stable complex with sAβ, reduces peptide degradation and may predispose to cerebrovascular and possibly enhance parenchymal amyloid formation under pathological conditions. 相似文献
14.
Peter Doering Meredin Stoltenberg Milena Penkowa J?rgen Rungby Agnete Larsen Gorm Danscher 《PloS one》2010,5(4)
Background
Traumatic brain injury (TBI) is one of the leading causes of disability and death among young people. Although much is already known about secondary brain damage the full range of brain tissue responses to TBI remains to be elucidated. A population of neurons located in cerebral areas associated with higher cognitive functions harbours a vesicular zinc pool co-localized with glutamate. This zinc enriched pool of synaptic vesicles has been hypothesized to take part in the injurious signalling cascade that follows pathological conditions such as seizures, ischemia and traumatic brain injury. Pathological release of excess zinc ions from pre-synaptic vesicles has been suggested to mediate cell damage/death to postsynaptic neurons.Methodology/Principal Findings
In order to substantiate the influence of vesicular zinc ions on TBI, we designed a study in which damage and zinc movements were analysed in several different ways. Twenty-four hours after TBI ZnT3-KO mice (mice without vesicular zinc) were compared to littermate Wild Type (WT) mice (mice with vesicular zinc) with regard to histopathology. Furthermore, in order to evaluate a possible neuro-protective dimension of chemical blocking of vesicular zinc, we treated lesioned mice with either DEDTC or selenite. Our study revealed that chemical blocking of vesicular zinc ions, either by chelation with DEDTC or accumulation in zinc-selenium nanocrystals, worsened the effects on the aftermath of TBI in the WT mice by increasing the number of necrotic and apoptotic cells within the first 24 hours after TBI, when compared to those of chemically untreated WT mice.Conclusion/Significance
ZnT3-KO mice revealed more damage after TBI compared to WT controls. Following treatment with DEDTC or selenium an increase in the number of both dead and apoptotic cells were seen in the controls within the first 24 hours after TBI while the degree of damage in the ZnT3-KO mice remained largely unchanged. Further analyses revealed that the damage development in the two mouse strains was almost identical after either zinc chelation or zinc complexion therapy. 相似文献15.
Chemokines and their receptors have been strongly implicated in the inflammatory process and pathogenesis of the neurodegenerative
disorders, such as Alzheimer’s disease (AD). In the present study, we examined the expression of chemokines, fractalkine,
interferon-inducible protein-10 (IP-10) and macrophage inflammatory protein-1α (MIP-1α) by immunohistochemistry in the brain
of transgenic mice APPSWE (Tg2576) at ages of 9, 11, and 17 months, which over-express a mutated form of human amyloid precursor protein (APP). Decreased
fractalkine and increased IP-10 expression in cerebral cortex and hippocampus were found at ages of 9 and 17 months in Tg2576
mice when compared with age-matched control mice. On the contrary, MIP-1α expression showed no difference between Tg2576 mice
and aged controls and was not influenced by ages. β-amyloid (Aβ) positive plaques were co-located with the intense IP-10 expression.
The finding suggests fractalkine and IP-10 may participate in the pathogenesis of AD; and could be new therapeutic strategies
for neuroprotection. 相似文献
16.
Lynn S. Perlmutter 《Molecular neurobiology》1994,9(1-3):33-40
Several factors have highlighted the vasculature in Alzheimer's disease (AD): Cerebral amyloid angiopathy (CAA) is common,
amyloid fibrils emanate from the vascular basement membrane (VBM), and similar forms of β-amyloid are found in vascular and
parenchymal amyloid accumulations. The present article discusses the presence of microvascular pathology in AD. Microangiopathy,
in addition to neurofibrillary tangles, senile plaques, and CAA, is a common pathologic hallmark of AD. VBM components are
associated with amyloid plaques, and nonamyloidotic alterations of the VBM occur in brain regions susceptible to AD lesions.
Also, intra-VBM perivascular cells (traditionally called pericytes), a subset of which share the immunophenotype of microglia
and other mononuclear phagocytic system (MPS) cells, have been implicated in vascular alterations and cerebrovascular amyloid
deposition. Perivascular and parenchymal MPS cells have access to several sources of the β-amyloid protein precursor, including
platelets, circulating white cells, and neurons. MPS cells would thus be ideally situated to uptake and process the precursor,
and deposit β-amyloid in a fashion analogous to that seen in other forms of systemic and cerebral amyloidoses. 相似文献
17.
Wahrle SE Jiang H Parsadanian M Hartman RE Bales KR Paul SM Holtzman DM 《The Journal of biological chemistry》2005,280(52):43236-43242
Apolipoprotein E (apoE) genotype has a major influence on the risk for Alzheimer disease (AD). Different apoE isoforms may alter AD pathogenesis via their interactions with the amyloid beta-peptide (Abeta). Mice lacking the lipid transporter ABCA1 were found to have markedly decreased levels and lipidation of apoE in the central nervous system. We hypothesized that if Abca1-/- mice were bred to the PDAPP mouse model of AD, PDAPP Abca1-/ mice would have a phenotype similar to that of PDAPP Apoe+/- and PDAPP Apoe-/- mice, which develop less amyloid deposition than PDAPP Apoe+/+ mice. In contrast to this prediction, 12-month-old PDAPP Abca -/- mice had significantly higher levels of hippocampal Abeta, and cerebral amyloid angiopathy was significantly more common compared with PDAPP Abca1+/+ mice. Amyloid precursor protein (APP) C-terminal fragments were not different between Abca1 genotypes prior to plaque deposition in 3-month-old PDAPP mice, suggesting that deletion of Abca1 did not affect APP processing or Abeta production. As expected, 3-month-old PDAPP Abca1-/- mice had decreased apoE levels, but they also had a higher percentage of carbonate-insoluble apoE, suggesting that poorly lipidated apoE is less soluble in vivo. We also found that 12-month-old PDAPP Abca1-/- mice had a higher percentage of carbonate-insoluble apoE and that apoE deposits co-localize with amyloid plaques, demonstrating that poorly lipidated apoE co-deposits with insoluble Abeta. Together, these data suggest that despite substantially lower apoE levels, poorly lipidated apoE produced in the absence of ABCA1 is strongly amyloidogenic in vivo. 相似文献
18.
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
19.
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
20.
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