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1.
Mitochondria and Neurodegeneration 总被引:2,自引:0,他引:2
Many lines of evidence suggest that mitochondria have a central role in ageing-related neurodegenerative diseases. However, despite the evidence of morphological, biochemical and molecular abnormalities in mitochondria in various tissues of patients with neurodegenerative disorders, the question “is mitochondrial dysfunction a necessary step in neurodegeneration?” is still unanswered. In this review, we highlight some of the major neurodegenerative disorders (Alzheimer’s disease, Parkinson’s disease, Amyotrophic lateral sclerosis and Huntington’s disease) and discuss the role of the mitochondria in the pathogenetic cascade leading to neurodegeneration. 相似文献
2.
Neurodegenerative diseases are a heterogeneous group of pathologies which includes complex multifactorial diseases, monogenic disorders and disorders for which inherited, sporadic and transmissible forms are known. Factors associated with predisposition and vulnerability to neurodegenerative disorders may be described usefully within the context of gene–environment interplay. There are many identified genetic determinants for neurodegeneration, and it is possible to duplicate many elements of recognized human neurodegenerative disorders in animal models of the disease. However, there are similarly several identifiable environmental influences on outcomes of the genetic defects; and the course of a progressive neurodegenerative disorder can be greatly modified by environmental elements. In this review we highlight some of the major neurodegenerative disorders (Alzheimer’s disease, Parkinson’s disease, Amyotrophic lateral sclerosis, Huntington’s disease, and prion diseases.) and discuss possible links of gene–environment interplay including, where implicated, mitochondrial genes. 相似文献
3.
The abnormal assembly and deposition of specific proteins in the brain is the probable cause of most neurodegenerative disease
afflicting the elderly. These “cerebral proteopathies” include Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s
disease (HD), prion diseases, and a variety of other disorders. Evidence is accumulating that the anomalous aggregation of
the proteins, and not a loss of protein function, is central to the pathogenesis of these diseases. Thus, therapeutic strategies
that reduce the production, accumulation, or polymerization of pathogenic proteins might be applicable to a wide range of
some of the most devastating diseases of old age. 相似文献
4.
Gaasch JA Geldenhuys WJ Lockman PR Allen DD Van der Schyf CJ 《Neurochemical research》2007,32(10):1686-1693
Recent studies suggest that iron enters cardiomyocytes via the L-type voltage-gated calcium channel (VGCC). The neuronal VGCC
may also provide iron entry. As with calcium, extraneous iron is associated with the pathology and progression of neurodegenerative
diseases such as Parkinson’s and Alzheimer’s disease. VGCCs, ubiquitously expressed, may be an important route of excessive
entry for both iron and calcium, contributing to cell toxicity or death. We evaluated the uptake of 45Ca2+ and 55Fe2+ into NGF-treated rat PC12, and murine N-2α cells. Iron not only competed with calcium for entry into these cells, but iron
uptake (similar to calcium uptake) was inhibited by nimodipine, a specific L-type VGCC blocker, and enhanced by FPL 64176,
an L-VGCC activator, in a dose-dependent manner. Taken together, these data suggest that voltage-gated calcium channels are
an alternate route for iron entry into neuronal cells under conditions that promote cellular iron overload toxicity.
Special issue dedicated to Dr. Moussa Youdim. 相似文献
5.
The understanding of oxidative damage in different neurodegenerative diseases could enhance therapeutic strategies. Our objective
was to quantify lipoperoxidation and other oxidative products as well as the activity of antioxidant enzymes and cofactors
in cerebrospinal fluid (CSF) samples. We recorded data from all new patients with a diagnosis of either one of the four most
frequent neurodegenerative diseases: Parkinson’s disease (PD), Alzheimer’s disease (AD), Huntington’s disease (HD) and lateral
amyotrophic sclerosis (ALS). The sum of nitrites and nitrates as end products of nitric oxide (NO) were increased in the four
degenerative diseases and fluorescent lipoperoxidation products in three (excepting ALS). A decreased Cu/Zn-dependent superoxide
dismutase (SOD) activity characterized the four diseases. A significantly decreased ferroxidase activity was found in PD,
HD and AD, agreeing with findings of iron deposition in these entities, while free copper was found to be increased in CSF
and appeared to be a good biomarker of PD. 相似文献
6.
Caricasole A Bakker A Copani A Nicoletti F Gaviraghi G Terstappen GC 《Bioscience reports》2005,25(5-6):309-327
Wnts function through the activation of at least three intracellular signal transduction pathways, of which the canonical
β-catenin mediated pathway is the best understood. Aberrant canonical Wnt signaling has been involved in both neurodegeneration
and cancer. An impairment of Wnt signals appears to be associated with aspects of neurodegenerative pathologies while overactivation
of Wnt signaling is a common theme in several types of human tumors. Therefore, although therapeutic approaches aimed at modulating
Wnt signaling in neurodegenerative and hyperproliferative diseases might impinge on the same molecular mechanisms, different
pharmacological outcomes are required. Here we review recent developments on the understanding of the role of Wnt signaling
in Alzheimer’s disease and CNS tumors, and identify possible avenues for therapeutic intervention within a complex and multi-faceted
signaling pathway. 相似文献
7.
Baolu Zhao 《Neurochemical research》2009,34(4):630-638
“Modern” medicine and pharmacology require an effective medical drug with a single compound for a specific disease. This seams
very scientific but usually has unavoidable side effects. For example, the chemical therapy to cancer can totally damage the
immunological ability of the patient leading to death early than non-treatment. On the other hand, natural antioxidant drugs
not only can cure the disease but also can enhance the immunological ability of the patient leading to healthier though they
usually have several compounds or a mixture. For the degenerative disease such as Alzheimer’s disease (AD) and Parkinson’s
disease (PD), natural antioxidant drugs are suitable drugs, because the pathogenesis of these diseases is complex with many
targets and pathways. These effects are more evidence when the clinic trial is for long term treatment. The author reviews
the studies on the protecting effects of natural antioxidants on neurons in neurodegenerative diseases, especially summarized
the results about protective effect of green tea polyphenols on neurons against apoptosis of cellular and animal PD models,
and of genestine and nicotine on neurons against Aβ—induced apoptosis of hippocampal neuronal and transgenic mouse AD models.
Special issue in honor of Dr. Akitane Mori. 相似文献
8.
Perego C Vanoni C Bossi M Massari S Basudev H Longhi R Pietrini G 《Journal of neurochemistry》2000,75(3):1076-1084
The GLT-1 and GLAST astroglial transporters are the glutamate transporters mainly involved in maintaining physiological extracellular glutamate concentrations. Defects in neurotransmitter glutamate transport may represent an important component of glutamate-induced neurodegenerative disorders (such as amyotrophic lateral sclerosis) and CNS insults (ischemia and epilepsy). We characterized the protein expression of GLT-1 and GLAST in primary astrocyte-neuron cocultures derived from rat hippocampal tissues during neuron differentiation/maturation. GLT-1 and GLAST are expressed by morphologically distinct glial fibrillary acidic protein-positive astrocytes, and their expression correlates with the status of neuron differentiation/maturation and activity. Up-regulation of the transporters paralleled the content of the synaptophysin synaptic vesicle marker p38, and down-regulation was a consequence of glutamate-induced neuronal death or the reduction of synaptic activity. Finally, soluble factors in neuronal-conditioned media prevented the down-regulation of the GLT-1 and GLAST proteins. Although other mechanisms may participate in regulating GLT-1 and GLAST in the CNS, our data indicate that soluble factors dependent on neuronal activity play a major regulating role in hippocampal cocultures. 相似文献
9.
Uberti D Bianchi I Olivari L Ferrari-Toninelli G Bonini SA Memo M 《Neurochemical research》2007,32(10):1726-1729
Dopaminergic agonists have been usually used as adjunctive therapy for the cure of Parkinson’s disease (PD). It is generally
believed that treatment with these drugs is symptomatic rather then curative and does not stop or delay the progression of
neuronal degeneration. However, several DA agonists of the DA D2–receptor family (including D2, D3 and D4-subtypes) have recently
been shown to possess neuroprotective properties in different in vitro and in vivo experimental PD models. Here we summarize
some recent data from our and other groups underlining the wide pharmacological spectrum of DA agonists currently used for
treating PD patients. In particular, the mechanism of action of different DA agonists does not appear to be restricted to
the stimulation of selective DA receptor subtypes being these drugs endowed with intrinsic, independent, and peculiar antioxidant
effects. This activity may represent an additional pharmacological property contributing to their clinical efficacy in PD.
Special issue dedicated to Dr. Moussa Youdim. 相似文献
10.
David H. Small 《Neurochemical research》2009,34(10):1824-1829
The accumulation of oligomeric species of β-amyloid protein in the brain is considered to be a key factor that causes Alzheimer’s
disease (AD). However, despite many years of research, the mechanism of neurotoxicity in AD remains obscure. Recent evidence
strongly supports the theory that Ca2+ dysregulation is involved in AD. Amyloid proteins have been found to induce Ca2+ influx into neurons, and studies on transgenic mice suggest that this Ca2+ influx may alter neuronal excitability. The identification of a risk factor gene for AD that may be involved in the regulation
of Ca2+ homeostasis and recent findings which suggest that presenilins may be involved in the regulation of intracellular Ca2+ stores provide converging lines of evidence that support the idea that Ca2+ dysregulation is a key step in the pathogenesis of AD.
Special issue article in Honor of Dr. Graham Johnston. 相似文献
11.
Mitochondrial Complex I [NADH Coenzyme Q (CoQ) oxidoreductase] is the least understood of respiratory complexes. In this review
we emphasize some novel findings on this enzyme that are of relevance to the pathogenesis of neurodegenerative diseases. Besides
CoQ, also oxygen may be an electron acceptor from the enzyme, with generation of superoxide radical in the mitochondrial matrix.
The site of superoxide generation is debated: we present evidence based on the rational use of several inhibitors that the
one-electron donor to oxygen is an iron-sulphur cluster, presumably N2. On this assumption we present a novel mechanism of
electron transfer to the acceptor, CoQ. Complex I is deeply involved in pathological changes, including neurodegeneration.
Complex I changes are involved in common neurological diseases of the adult and old ages. Mitochondrial cytopathies due to
mutations of either nuclear or mitochondrial DNA may represent a useful model of neurodegeneration. In this review we discuss
Parkinson’s disease, where the pathogenic involvement of Complex I is better understood; the accumulated evidence on the mode
of action of Complex I inhibitors and their effect on oxygen radical generation is discussed in terms of the aetiology and
pathogenesis of the disease.
Special issue article in honor of Dr. Anna Maria Giuffrida-Stella. 相似文献
12.
Several lines of evidence support the neuroprotective action of cyclooxygenase-2 (COX-2) inhibitors in various models of Parkinson’s
disease (PD). In the current study, we investigated the neuroprotective properties of several COX inhibitors against 1-methyl-4-phenylpyridinium
(MPP+) in neuroblastoma Neuro 2A (N-2A) cells in vitro and the protection against degeneration of substantia nigra pars compacta
(SNc) dopaminergic (DA) neurons after the administration of 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine (MPTP) in C57/BL6
male mice. The data obtained demonstrate a lack of protective effects observed by COX 1-2 inhibitors ibuprofen and acetylsalicylic
acid against MPP+ toxicity in N-2A, where piroxicam was protective in a dose dependent manner (MPP+ control: 15 ± 2% MPP+
piroxicam: 5 mM 89 ± 4%). The data also indicate a drop in mitochondrial oxygen (O2) consumption and ATP during MPP+ toxicity with no restoration of mitochondrial function concurrent to a heightened concentration
of somatic ATP during piroxicam rescue. These findings indicate that the neuroprotective effects of COX inhibitors against
MPP+ are not consistent, but that piroxicam may work through an unique mechanism to propel anaerobic energy metabolism. On
the other hand, using mice, piroxicam (20 mg/kg) was effective against MPTP-induced dopaminergic degeneration in the (SNc)
and loss of locomotive function in mice. Administering a 3 day pre-treatment of piroxicam (20 mg/kg) was effective in antagonizing
the losses in SNc tyrosine hydroxylase protein expression, SNc DA concentration and associated anomaly in ambulatory locomotor
activity. It was concluded from these findings that piroxicam is unique among COX inhibitors in providing very significant
neuroprotection against MPP+ in vitro and in vivo. 相似文献
13.
W. D. Ehmann W. R. Markesbery E. J. Kasarskis D. E. Vance S. S. Khare J. D. Hord C. M. Thompson 《Biological trace element research》1987,13(1):19-33
Although the etiology and pathogenesis of Alzheimer’s disease, Pick’s disease, and amyotrophic lateral sclerosis are still
unknown, it has been suggested that perturbations in element metabolism may play a role. Even if not causative factors, these
imbalances may prove to be markers that could aid in diagnosis. We have employed a sequential neutron activation analysis
(NAA) procedure to determine elemental concentrations in brain, hair, fingernails, blood, and cerebrospinal fluid (CSF) of
these patients and age-matched controls. Samples are first irradiated with accelerator-produced 14-MeV neutrons for determination
of nitrogen and phosphorus, then with reactor thermal neutrons for the instrumental determination of 16–18 minor and trace
elements, and, finally, reactor-irradiated again, followed by a rapid radiochemical separation procedure (RNAA) to determine
four additional elements. Major advantages of NAA are: (1) its simultaneous multielement capability; (2) the relative freedom
from reagent and laboratory contamination; (3) the absence of major matrix effects; and (4) an adequate sensitivity for most
elements of interest. Ranges of concentrations by INAA and RNAA in selected control tissues and interelement correlations
in control brain are presented to illustrate results obtained by the procedure. Longitudinal studies of tissues from Alzheimer’s
disease (AD) and amyotrophic lateral sclerosis (ALS) patients are still in progress. 相似文献
14.
The ART of Loss: Aβ Imaging in the Evaluation of Alzheimer’s Disease and other Dementias 总被引:1,自引:0,他引:1
Villemagne VL Fodero-Tavoletti MT Pike KE Cappai R Masters CL Rowe CC 《Molecular neurobiology》2008,38(1):1-15
Molecular neuroimaging based on annihilation radiation tomographic (ART) techniques such as positron emission tomography (PET), in conjunction with related biomarkers in plasma and cerebrospinal fluid (CSF), are proving valuable in the early and differential diagnosis of Alzheimer's disease (AD). With the advent of new therapeutic strategies aimed at reducing beta-amyloid (Abeta) burden in the brain to potentially prevent or delay functional and irreversible cognitive loss, there is increased interest in developing agents that allow assessment of Abeta burden in vivo. Abeta burden as assessed by molecular imaging matches histopathological reports of Abeta plaque distribution in aging and dementia and appears more accurate than FDG for the diagnosis of AD. Abeta imaging is also a very powerful tool in the differential diagnosis of AD from fronto-temporal dementia (FTD). Although Abeta burden as assessed by PET does not correlate with measures of cognitive decline in AD, it does correlate with memory impairment and rate of memory decline in mild cognitive impairment (MCI) and healthy older subjects. Approximately 30% of asymptomatic controls present cortical (11)C-PiB retention. These observations suggest that Abeta deposition is not part of normal ageing, supporting the hypothesis that Abeta deposition occurs well before the onset of symptoms and is likely to represent preclinical AD. Further longitudinal observations are required to confirm this hypothesis and to better elucidate the role of Abeta deposition in the course of Alzheimer's disease. 相似文献
15.
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
16.
Leucine-rich repeat kinase 2 (LRRK2) is a member of the ROCO protein superfamily (Ras of complex proteins (Roc) with a C-terminal
Roc domain). Mutations in the LRRK2 gene lead to autosomal dominant Parkinsonism. We have cloned the porcine LRRK2 cDNA in an attempt to characterize conserved and therefore likely functional domains. The LRRK2 cDNA contains an open reading frame of 7,578 bp. The predicted LRRK2 protein consists of 2,526 amino acids of 86–93% identity
with its mammalian couterparts. The deduced amino acid sequence of encoded porcine LRRK2 protein displays extensive homology
with its human counterpart, with greatest similarities in those regions that contain the kinase domain, the Roc domain and
the COR motif. Expression of porcine LRRK2 mRNA in various organs and tissues is similar to its human counterpart and not limited to the brain. The obtained data show
that the LRRK2 sequence and expression patterns are conserved across species. The porcine LRRK2 gene was mapped to chromosome 5q25. The results obtained suggest that the LRRK2 gene might be of particular interest in our attempt to generate a transgenic porcine model for Parkinson’s disease.
The sequence of the porcine LRRK2 cDNA, encoding the LRRK2/dardarin protein, and the genomic sequence of LRRK2 have been submitted to DDBJ/EMBL/GenBank under the Accessions Numbers EU019992, and EU019994, respectively. 相似文献
17.
Majumder P Raychaudhuri S Chattopadhyay B Bhattacharyya NP 《Cellular and molecular neurobiology》2007,27(8):1127-1145
(1) Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease caused by the expansion of polymorphic CAG
repeats beyond 36 at exon 1 of huntingtin gene (htt). To study cellular effects by expressing N-terminal domain of Huntingtin (Htt) in specific cell lines, we expressed exon
1 of htt that codes for 40 glutamines (40Q) and 16Q in Neuro2A and HeLa cells. (2) Aggregates and various apoptotic markers were detected
at various time points after transfection. In addition, we checked the alterations of expressions of few apoptotic genes by
RT-PCR. (3) Cells expressing exon 1 of htt coding 40Q at a stretch exhibited nuclear and cytoplasmic aggregates, increased caspase-1, caspase-2, caspase-8, caspase-9/6,
and calpain activations, release of cytochrome c and AIF from mitochondria in a time-dependent manner. Truncation of Bid was increased, while the activity of mitochondrial
complex II was decreased in such cells. These changes were significantly higher in cells expressing N-terminal Htt with 40Q
than that obtained in cells expressing N-terminal Htt with 16Q. Expressions of caspase-1, caspase-2, caspase-3, caspase-7,
and caspase-8 were increased while expression of Bcl-2 was decreased in cells expressing mutated Htt-exon 1. (4) Results presented
in this communication showed that expression of mutated Htt-exon 1 could mimic the cellular phenotypes observed in Huntington’s
disease and this cell model can be used for screening the agents that would interfere with the apoptotic pathway and aggregate
formation. 相似文献
18.
19.
Parkinson’s disease (PD) is a progressive neurodegenerative disorder with a prevalence of 1–2% in people over the age of 50.
Mitochondrial dysfunction occurred in PD patients showing a 15–30% loss of activity in complex I. Asiatic acid (AA), a triterpenoid,
is an antioxidant and used for depression treatment, but the effect of AA against PD-like damage has never been reported.
In the present study, we investigated the protective effects of AA against H2O2 or rotenone-induced cellular injury and mitochondrial dysfunction in SH-SY5Y cells. Mitochondrial membrane potential (MMP)
and the expression of voltage-dependent anion channel (VDAC) were detected with or without AA pretreatment following cellular
injury to address the possible mechanisms of AA neuroprotection. The results showed that pre-treatment of AA (0.01–100 nM)
protected cells against the toxicity induced by rotenone or H2O2. In addition, MMP dissipation occurred following the exposure of rotenone, which could be prevented by AA treatment. More
interestingly, pre-administration of AA inhibited the elevation of VDAC mRNA and protein levels induced by rotenone(100 nM)
or H2O2 (300 μM).These data indicate that AA could protect neuronal cells against mitochondrial dysfunctional injury and suggest
that AA might be developed as an agent for PD prevention or therapy.
Special issue article in honor of Dr. Akitane Mori. 相似文献
20.
Cotman CW 《Neurochemical research》2005,30(6-7):877-881
During brain aging and progression of Alzheimer’s disease, the levels of Aβ and proinflammatory cytokines accumulate very
early in the pathogenic process prior to any major degenerative changes. Accumulation of these molecules may impair with signal
transduction pathways critical for neuronal health. Neurotrophin signaling is a critical mechanism involved in synaptic plasticity,
learning and memory and neuronal health. We have recently shown that exposure to low levels of Aβ impairs BDNF trkB signal
transduction, suppressing the Ras/ERK, and the PI3-K/Akt pathways but not the PLCγ pathway. As a result, downstream regulation
of gene expression and neuronal viability are impaired. Recently, we have found that at least three agents – Aβ, TNFα, Il-1β
– suppress TrkB signaling and act via a common and novel mechanism. These factors all regulate the docking proteins (e.g.,
IRS and Shc) that link the activated Trk receptor to downstream effectors. While this is a novel mechanism underlying regulation
of Trk signaling, such a mechanism has been identified for the insulin/IGF-1 receptor in the presence of proinflammatory cytokines
and is one of the mechanisms for insulin/IGF-resistance, which is a key risk factor for type II diabetes (1). We suggest that accumulation of AB and proinflammatory cytokines during aging generates in the brain a “neurotrophin resistance”
state that places the brain at risk for cognitive decline and dementia. 相似文献