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1.
(1) Huperzine A, a promising therapeutic agent for Alzheimer’s disease (AD), was tested for its effects on cholinergic and
monoaminergic dysfunction induced by injecting β-amyloid peptide-(1–40) into nucleus basalis magnocellularis of the rat. (2)
Bilateral injection of 10 μg β-amyloid peptide-(1–40) into nucleus basalis magnocellularis produced local deposits of amyloid
plaque and functional abnormalities detected by microdialysis. In medial prefrontal cortex, reductions in the basal levels
and stimulated release of acetylcholine, dopamine, norepinephrine, and 5-hydroxytryptamine were observed. However, oral huperzine
A (0.18 mg/kg, once daily for 21 consecutive days) markedly reduced morphologic abnormalities at the injection site in rats
infused with β-amyloid peptide-(1–40). Likewise, this treatment ameliorated the β-amyloid peptide-(1–40)-induced deficits
in extracellular acetylcholine, dopamine, and norepinephrine (though not 5-hydroxytryptamine) in medial prefrontal cortex,
and lessened the reduction in nicotine or methoctramine-stimulated release of acetylcholine and K+-evoked releases of acetylcholine and dopamine. (3) The present results provide the first direct evidence that huperzine A
acts to oppose neurotoxic effects of β-amyloid peptide on cholinergic, dopaminergic, and noradrenergic systems of the rat
forebrain. 相似文献
2.
Schliebs R 《Neurochemical research》2005,30(6-7):895-908
Alzheimer’s disease, the most common neurodegenerative disorder of senile dementia, is characterized by two major morpho-pathological
hallmarks. Deposition of extracellular neuritic, β-amyloid peptide-containing plaques (senile plaques) in cerebral cortical
regions of Alzheimer patients is accompanied by the presence of intracellular neurofibrillary tangles in cerebral pyramidal
neurons. Basal forebrain cholinergic dysfunction is also a consistent feature of Alzheimer’s disease, which has been suggested
to cause, at least partly, the cognitive deficits observed in patients with Alzheimer’s disease. Impaired cortical cholinergic
neurotransmission may also contribute to β-amyloid plaque pathology in Alzheimer’s disease by affecting expression and processing
of the β-amyloid precursor protein (APP). Vice versa, low level of soluble β-amyloid has been observed to inhibit cholinergic
synaptic function. Deposition of β-amyloid plaques in Alzheimer’s disease is also accompanied by a significant plaque-associated
glial up-regulation of interleukin-1, which has been attributed to affect expression and metabolism of APP and to interfere
with cholinergic transmission. Understanding the molecular mechanisms underlying the interrelationship between cortical cholinergic
dysfunction, β-amyloid formation and deposition, as well as local inflammatory upregulation, would allow to derive potential
treatment strategies to pharmacologically intervene in the disease-causing signaling cascade. 相似文献
3.
Association between the PI*M3 allele of α1-antitrypsin and Alzheimer’s disease? A preliminary report
A. Kowalska Heidi Danker-Hopfe Mieczyslaw Wender Jolanta Florczak Hubert Walter 《Human genetics》1996,98(6):744-746
The deposition of βA4-amyloid in senile plaques in the brain and small cerebral vessels is one of the pathological hallmarks
of Alzheimer’s disease (AD). Serine protease inhibitors (serpins) such as α1-antitrypsin and α1-antichymotrypsin have been
found to be associated with β-amyloid deposits; interest in their role in the pathogenesis of AD has therefore recently increased.
We have analyzed α1-antitrypsin phenotypes in a sample of 29 Polish patients with probable Alzheimer’s disease. We have found
an increased frequency of the PI*M3 allele (0.1897) in patients in comparison with the general population control (0.0563).
Received: 8 May 1996 / Revised 28 June 1996 相似文献
4.
Wang ZF Yan J Fu Y Tang XC Feng S He XC Bai DL 《Cellular and molecular neurobiology》2008,28(2):245-261
(1) This study was to evaluate the anti-cholinesterase (ChE), cognition enhancing and neuroprotective effects of FS-0311,
a bis-huperzine B derivative. (2) ChE activity was evaluated using a spectrophotometric method. Cognitive deficits in mice
were induced by scopolamine or transient brain ischemia and reperfusion. Water maze was used to detect the cognitive performance.
PC12 cell injury was induced by β-amyloid 25–35 (Aβ25–35), oxygen-glucose deprivation (OGD), or staurosporine treatment. (3) FS-0311 was a potent, highly specific inhibitor of acetylcholinesterase
(AChE). FS-0311 bound to AChE in a reversible manner, causing linear mixed-type inhibition. FS-0311 had a high oral bioavailability
and a long duration of AChE inhibitory action in vivo. FS-0311 was found to antagonize cognitive deficits induced by scopolamine
or transient brain ischemia and reperfusion in a water maze task. FS-0311 possessed the ability to protect PC12 cells against
Aβ25–35 peptide toxicity, OGD insult and staurosporine-induced apoptosis. The neuroprotective effects of FS-0311 appeared to reflect
an attenuation of oxidative stress. (4) With the profile of anti-ChE and neuroprotective activities, FS-0311 might be a promising
candidate in neurodegenerative diseases, such as Alzheimer’s disease and Vascular dementia. 相似文献
5.
Nie H Li Z Lukas RJ Shen Y Song L Wang X Yin M 《Cellular and molecular neurobiology》2008,28(1):103-112
(1) Nicotinic acetylcholine receptors in central nervous system are thought to be new targets for Alzheimer’s disease. However,
the most involved nicotinic receptor subtype in Alzheimer’s disease is unclear. α4β2 receptor is the most widely spread subtype
in brain, involving in several important aspects of cognitive and other functions. We constructed cell line by transfecting
human amyloid precursor protein (695) gene into SH-EP1 cells which have been transfected with human nicotinic receptor α4
subunit and β2 subunit gene, to observe effects of α4β2 receptors activation on β-amyloid, expecting to provide a new cell
line for drug screening and research purpose. (2) Liposome transfection was used to express human amyloid precursor protein
(695) gene in SH-EP1-α4β2 cells. Function of the transfected α4β2 receptors was tested by patch clamp. Effects of nicotine
and epibatidine (selective α4β2 nicotinic receptor agonist) on β-amyloid were detected by Western blot and ELISA. Effects
of nicotine and epibatidine on amyloid precursor protein (695) mRNA level were measured using real-time PCR. (3) Human amyloid
precursor protein (695) gene was stably expressed in SH-EP1-α4β2 cells; Nicotine (1 μM) and epibatidine (0.1 μM) decreased
intracellular and secreted β-amyloid in the cells; and activation of α4β2 receptors did not affect amyloid precursor protein
(695) mRNA level. (4) These results suggest that the constructed cell line, expressing both amyloid precursor protein (695)
gene and human nicotinic receptor α4 subunit and β2 subunit gene, might be useful for screening specific nicotinic receptor
agonists against Alzheimer’s disease. Alteration of Aβ level induced by activation of α4β2 nAChR in our study might occur
at a post-translational level. 相似文献
6.
Alzheimer’s disease is the most common form of dementia in the elderly, and is characterised by extracellular amyloid plaques
composed of the β-amyloid peptide (Aβ). However, disease progression has been shown to correlate more closely with the level
of soluble Aβ oligomers. Recent evidence suggests that these oligomers are covalently crosslinked, possibly due to the interaction
of Aβ with redox-active metal ions. These findings offer new avenues for the treatment and prevention of disease, by modulating
metal binding or preventing the formation of neurotoxic Aβ oligomers.
Australian Society for Biophysics Special Issue: Metals and Membranes in Neuroscience. 相似文献
7.
Kedar N. Prasad Francisco G. La Rosa Judith E. Prasad 《In vitro cellular & developmental biology. Animal》1998,34(3):265-274
Summary Although chronic inflammatory reactions have been proposed to cause neuronal degeneration associated with Alzheimer’s disease
(AD), the role of prostaglandins (PGs), one of the secretory products of inflammatory reactions, in degeneration of nerve
cells has not been studied. Our initial observation that PGE1-induced differentiated neuroblastoma (NB) cells degenerate in vitro more rapidly than those induced by RO20-1724, an inhibitor of cyclic nucleotide phosphodiesterase, has led us to postulate
that PGs act as a neurotoxin. This study has further investigated the effects of PGs on differentiated NB cells in culture.
Results showed that PGA1 was more effective than PGE1 in causing degeneration of differentiated NB cells as shown by the cytoplasmic vacuolation and fragmentation of soma, nuclei,
and neurites. Because increased levels of ubiquitin and β-amyloid have been implicated in causing neuronal degeneration, we
studied the effects of PGs on the levels of these proteins during degeneration of NB cells in vitro by an immunostaining technique, using primary antibodies to ubiquitin and β-amyloid. Results showed that PGs increased the
intracellular levels of ubiquitin and β-amyloid prior to degeneration, whereas the degenerated NB cells had negligible levels
of these proteins. These data suggest that PGs act as external neurotoxic signals which increase levels of ubiquitin and β-amyloid
that represent one of the intracellular signals for initiating degeneration of nerve cells. 相似文献
8.
Juan Li Jinjia Hu Biyun Shao Wei Zhou Yongyao Cui Changzhi Dong Jean-Marc Miezan Ezoulin Xu Zhu Wenlong Ding Françoise Heymans Hongzhuan Chen 《Cellular and molecular neurobiology》2009,29(4):589-595
Amyloid-β (Aβ) plays a central role in the neuroinflammation and cholinergic neuronal apoptosis in Alzheimer’s disease, and
thus has been considered as a main determinant of this disease. In the previous study, we reported that PMS777, a novel bis-interacting
ligand for acetylcholinesterase (AChE) inhibition and platelet-activating factor (PAF) receptor antagonism, could significantly
attenuate PAF-induced neurotoxicity. Continuing our efforts, we further investigated the protective effect of PMS777 on Aβ-induced
neuronal apoptosis in vitro and neuroinflammation in vivo. PMS777 (1–100 μM) was found to inhibit Aβ-induced human neuroblastoma
SH-SY5Y cell apoptosis in a concentration-dependent manner. Concurrently, PMS777 increased ratio of bcl-2 to bax mRNA, and
inhibited both mRNA expression and activity of caspase-3 in SH-SY5Y cells after the exposure with Aβ. In vivo experimental
study demonstrated that PMS777 could attenuate Aβ-induced microglial and astrocytic activation in the rat hippocampus after
systemic administration. These results suggest that PMS777 potently protects against Aβ-induced neuronal apoptosis and neuroinflammation,
and warrants further investigations in connection with its potential value in the treatment of Alzheimer’s disease.
The authors Juan Li and Jinjia Hu contributed equally to this article. 相似文献
9.
Pathogenesis of Alzheimer’s disease (AD), which is characterised by accumulation of extracellular deposits of β-amyloid peptide
(Aβ) in the brain, has recently been linked to vascular disorders such as ischemia and stroke. Aβ is constantly produced in
the brain from amyloid precursor protein (APP) through its cleavage by β- and γ-secretases and certain Aβ species are toxic
for neurones. The brain has an endogenous mechanism of Aβ removal via proteolytic degradation and the zinc metalloproteinase
neprilysin (NEP) is a critical regulator of Aβ concentration. Down-regulation of NEP could predispose to AD. By comparing
the effects of hypoxia and oxidative stress on expression and activity of the Aβ-degrading enzyme NEP in human neuroblastoma
NB7 cells and rat primary cortical neurones we have demonstrated that hypoxia reduced NEP expression at the protein and mRNA
levels as well as its activity. On contrary in astrocytes hypoxia increased NEP mRNA expression.
Special issue dedicated to Dr. Moussa Youdim. 相似文献
10.
Stephen D. Skaper Nicholas A. Evans Peter E. Soden Claudia Rosin Laura Facci Jill C. Richardson 《Neurochemical research》2009,34(12):2243-2250
Alzheimer’s disease is characterised by regional neuronal degeneration, synaptic loss, and the progressive deposition of the
4 kDa β-amyloid peptide (Aβ) in senile plaques and accumulation of tau protein as neurofibrillary tangles. Aβ derives from
the larger precursor molecule, amyloid precursor protein (APP) by proteolytic processing via β- and γ-secretases. While APP
expression is well documented in neurons and astrocytes, the case for oligodendrocytes is less clear. The latter cell type
is reported to express different isoforms of APP, and we have confirmed this observation by immunocytochemistry in cultures
of differentiated rat cortical oligodendrocytes. Moreover, by means of a sensitive electrochemiluminescent immunoassay employing
Aβ C-terminal specific antibodies, mature oligodendrocytes are shown to secrete the 40 and 42 amino acid Aβ species (Aβ40
and Aβ42). Secretion of Aβ peptides was reduced by incubating oligodendrocytes with α- and β-secretase inhibitors, or a γ-secretase
inhibitor. Disturbances of APP processing and/or synthesis in oligodendrocytes may account for some myelin disorders observed
in Alzheimer’s disease and other senile dementias. 相似文献
11.
Fredrik Haeffner Kevin J. Barnham Ashley I. Bush Tore Brinck 《Journal of molecular modeling》2010,16(6):1103-1108
A mechanism for the oxidation of a dimeric β-amyloid copper ion complex is proposed based on DFT calculations. It involves
the Met35 residue, which is believed to be important in the neurotoxicity causing Alzheimer’s disease. Oxidation of Met35
is found to proceed readily with dioxygen when two Met35 residues are close to each other and the copper ion. This indicates
that oxidants, such as hydrogen peroxide, are not necessary for oxidation of β-amyloid copper ion complexes. Understanding
these processes could be pivotal in gaining more knowledge of this complex disease and for the development of therapeutic
treatments. 相似文献
12.
A two-wave technique of calciometry with the use of a fluorescence dye, fura-2/AM, was applied for examination of the effect
of a protein, β-amyloid (the main component of senile plaques in Alzheimer’s disease), on calcium homeostasis in cultured
neurons of the rat hippocampus; β-amyloid was added to the culture medium. In most neurons, the effect of β-amyloid appeared
as a more than twofold increase in the basic calcium concentration, as compared with the control (153.4 ± 11.5 and 71.7 ±
5.4 nM, respectively; P < 0.05). The characteristics of calcium transients induced by application of hyperpotassium solution also changed; the amplitude
of these transients decreased, and the duration of a part corresponding to calcium release from the cell (rundown of the transient)
increased. The mean amplitude of calcium transients under control conditions was 447.5 ± 20.1 nM, while after incubation in
the presence of β-amyloid this index dropped to 278.4 ± 22.6 nM. Under control conditions, the decline phase of calcium transients
lasted, on average, 100 ± 6 sec, while after incubation of hippocampal cell cultures in the presence of β-amyloid this phase
lasted 250 ± 10 sec. Therefore, an excess of β-amyloid influences significantly calcium homeostasis in the nerve cells by
disturbing functions of the calcium-controlling systems, such as voltage-operated calcium channels of the plasma membrane
and calcium stores of the mitochondria and endoplasmic reticulum.
Neirofiziologiya/Neurophysiology, Vol. 40, No. 1, pp. 9–12, January–February, 2008. 相似文献
13.
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
14.
15.
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
16.
Costanzi E Martino S Persichetti E Tiribuzi R Massini C Bernardi G Orlacchio A Orlacchio A 《Neurochemical research》2008,33(12):2510-2515
Several therapies for Alzheimer’s Disease (AD) are currently under investigation. Some studies have reported that concentration
of vitamins in biological fluids are lower in AD patients compared to control subjects and clinical evidence has shown the
therapeutic potential of vitamin C and E in delaying AD progression. However, the molecular mechanism(s) that are engaged
upon their administration in the APP metabolism in vitro or in vivo still need clarifying. Here, we investigate the effects
of vitamin C supplementation, at physiological concentration, in skin fibroblasts obtained from SAD and FAD patients. This
study shows that SAD patients’ fibroblasts exhibited the exclusive appearance of C-terminal fragments, derived from APP processing,
without giving rise to the β-amyloid peptide, other than corresponding decreased levels of lysosomal enzymes, such as β-hexosaminidase,
α-mannosidase and cathepsins B, L, and D.
Special issue article in honor of Anna Maria Giuffrida-Stella. 相似文献
17.
Alzheimer’s disease is characterised by the inappropriate death of brain cells and accumulation of the Aβ peptide in the brain.
Thus, it is possible that there are fundamental differences between Alzheimer’s disease patients and healthy individuals in
their abilities to clear Aβ from brain fluid and to protect neurons from Aβ toxicity. In the present study, we examined (1)
the cytotoxicity of Alzheimer’s disease cerebrospinal fluid (CSF) compared to control CSF, (2) the ability of Alzheimer’s
disease and control CSF to protect cells from Aβ toxicity and to promote cell-mediated clearance of Aβ and lastly (3) the
effects of extracellular chaperones, normally found in CSF, on these processes. We show that the Alzheimer’s disease CSF samples
tested were more toxic to cultured neuroblastoma cells than normal CSF. In addition, the Alzheimer’s disease CSF samples tested
were less able to protect cells from Aβ-induced toxicity and less efficient at promoting macrophage-like cell uptake when
compared to normal CSF. The addition of physiologically relevant concentrations of the extracellular chaperones, clusterin,
haptoglobin and α2-macroglobulin into CSF protected neuroblastoma cells from Αβ1-42 toxicity and promoted Αβ1-42 uptake in macrophage-like cells. These results suggest that extracellular chaperones are an important element of a system
of extracellular protein folding quality control that protects against Aβ toxicity and accumulation. 相似文献
18.
Peter Kreutzmann Gerald Wolf Kathleen Kupsch 《Cellular and molecular neurobiology》2010,30(7):979-984
Minocycline, a tetracycline antibiotic, has been reported to exert beneficial effects in models of Alzheimer’s disease (AD).
To characterize the mechanisms underlying the putative minocycline-related neuroprotection, we studied its effect in an in
vitro model of AD. Primary hippocampal cultures were treated with β-amyloid peptide (Aβ) and cell viability was assessed by
standard MTT-assay. Incubation with 10 μM Aβ for 24 h significantly inhibits cellular MTT-reduction without inducing morphological
signs of enhanced cell death or increase in release of lactate dehydrogenase. This indicates that cell viability was not affected.
The inhibition of MTT-reduction by Aβ was due to an acceleration of MTT-formazan exocytosis. Intriguingly, the Aβ-triggered
increase in MTT-formazan exocytosis was abolished by co-treatment with minocycline. In vehicle-treated cells minocycline had
no effect on formazan exocytosis. This hitherto unrecognized property of minocycline has to be noticed in the elucidation
of the underlying mechanism of this promising neuroprotectant. 相似文献
19.
Akira Matsumoto Reiko Matsumoto Kei-ichi Kadoyama Taka-aki Nishimoto Shogo Matsuyama Osamu Midorikawa 《International journal of peptide research and therapeutics》2009,15(3):205-210
Establishment of diagnostic measures for early stage Alzheimer’s disease (AD) and mild cognitive impairment (MCI) is of crucial
importance. Using surface enhanced laser desorption ionization time-of-flight mass spectrometry (SELDI-TOF-MS), antibody-assisted
MS of cerebrospinal fluid (CSF) has enabled quantitative analysis of the ratio of β-amyloid (Aβ) peptides, Aβ1-42/Aβ1-40,
which has a diagnostic value for AD/MCI. To apply the MS analysis to a far wider range of CSF samples, we have established
a method to analyze Aβ peptides expressed in 100 μl CSF samples quantitatively. Pretreatment of CSF samples by limit-filtration
to condense peptides, and modified washing procedure using urea as denaturant, Aβ peptides of interest can be assessed with
higher sensitivity by five to tenfolds to the original method. This improvement enables quantitative analysis of Aβ species
from a residual amount of CSF samples, which will be occasionally obtained in case of lumbar anesthesia prior to operation
and spinal tap performed for routine diagnostic purposes. Prevalence of the new procedure as laboratory test, especially among
the elderly consulting for neurological clinic, will enhance the number of subjects diagnosed at early stage of AD/MCI. 相似文献
20.
The so-called “cholinergic hypothesis” assumes that degenerative dysfunction of the cholinergic system originating in the
basal forebrain and innervating several cortical regions and the hippocampus, is related to memory impairment and neurodegeneration
found in several forms of dementia and in brain aging. Biochemical methods measuring the activity of the key enzyme for acetylcholine
synthesis, choline acetyltransferase, have been used for many years as a reliable marker of the integrity or the damage of
the cholinergic pathways. Stereologic counting of the basal forebrain cholinergic cell bodies, has been additionally used
to assess neurodegenerative changes of the forebrain cholinergic system. While initially believed to mark relatively early
stages of disease, cholinergic dysfunction is at present considered to occur in advanced dementia of Alzheimer’s type, while
its involvement in mild and prodromal stages of the disease has been questioned. The issue is relevant to better understand
the neuropathological basis of the diseases, but it is also of primary importance for therapy. During the last few years,
indeed, cholinergic replacement therapies, mainly based on the use of acetylcholinesterase inhibitors to increase synaptic
availability of acetylcholine, have been exploited on the assumption that they could ameliorate the progression of the dementia
from its initial stages. In the present paper, we review data from human studies, as well as from animal models of Alzheimer’s
and Down’s diseases, focusing on different ways to evaluate cholinergic dysfunction, also in relation to the time point at
which these dysfunctions can be demonstrated, and on some discrepancy arising from the use of different methodological approaches.
The reviewed literature, as well as some recent data from our laboratories on a mouse model of Down’s syndrome, stress the
importance of performing biochemical evaluation of choline acetyltransferase activity to assess cholinergic dysfunction both
in humans and in animal models.
Special issue article in honor of Dr. Frode Fonnum. 相似文献