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1.
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
2.
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
3.
Transport defects may arise in various neurodegenerative diseases from failures in molecular motors, microtubule abnormalities,
and the chaperone/proteasomal degradation pathway leading to aggresomal-lysosomal accumulations. These defects represent important
steps in the neurodegenerative cascade, although in many cases, a clear consensus has yet to be reached regarding their causal
relationship to the disease. A growing body of evidence lends support to a link between neurite transport defects in the very
early stages of many neurodegenerative diseases and alterations in the organization and dynamics of the actin cytoskeleton
initiated by filament dynamizing proteins in the ADF/cofilin family. This article focuses on cofilin, which in neurons under
stress, including stress induced by the amyloid-β (Aβ) 1–42 peptide, undergoes dephosphorylation (activation) and forms rod-shaped
actin boundles (rods). Rods inhibit transport, are sites of amyloid precursor protein accumulation, and contribute to the
pathology of Alzheimer’s disease. Because rods form rapidly in response to anoxia, they could also contribute to synaptic
deficits associated with ischemic brain injury (e.g., stroke). Surprisingly, cofilin undergoes phosphorylation (inactivation)
in hippocampal neurons treated with Aβ1–40 at high concentrations, and these neurons undergo dystrophic morphological changes, including accumulation of pretangle phosphorylated-τ. Therefore, extremes in phosphoregulation of cofilin by different forms of Aβ may explain much of the Alzheimer’s disease
pathology and provide mechanisms for synaptic loss and plaque expansion.
An erratum to this article is available at . 相似文献
4.
In China, it has been estimated that there are more than 2.0 million people suffering from Parkinson’s disease, which is currently
becoming one of the most common chronic neurodegenerative disorders during recent years. For many years, scientists have struggled
to find new therapeutic approaches for this disease. Since 1994, our research group led by Drs. Ji-Sheng Han and Xiao-Min
Wang of Neuroscience Research Institute, Peking University has developed several prospective treatment strategies for the
disease. These studies cover the traditional Chinese medicine—herbal formula or acupuncture, and modern technologies such
as gene therapy or stem cell replacement therapy, and have achieved some original results. It hopes that these data may be
beneficial for the research development and for the future clinical utility for treatment of Parkinson’s disease.
Special issue article in honor of Dr. Ji-Sheng Han. 相似文献
5.
Correlations between indices of P300 EEG potential,cognitive tests,and variational pulsometry in Parkinsonian patients 总被引:1,自引:1,他引:0
The parameters of an event-related EEG potential (ERP), P300 wave, are now extensively used as objective neurophysiological
indices of the state of cognitive functions. At the same time, information on the effects of the autonomic nervous system
on the parameters of P300 is limited. In Parkinson’s disease clinics, in addition to the leading motor disorders, more or
less clear psychoemotional, cognitive, and autonomic (in particular cardiovascular) impairments are usually observed. This
allows one to study the dependence between the cardiovascular dysfunction and intensity of cognitive disorders in Parkinsonian
patients. In our study on this contingent, we analyzed correlations between the parameters of P300 potential, indices of the
state of the cognitive sphere (determined using a questionnaire, Mini Mental State Examination, MMSE, and a Luriya’s test),
and indices of variational pulsometry. Thirty-five Parkinsonian patients (49 to 74 years, severity of disease 1.5 to 3.0 by
the international classification) were examined. We found a negative influence of excessive sympathetic tonus in cardiovascular
control on the state of cognitive functions. The latency of P300 potential was longer in patients with greater intensities
of sympathetic influences on the cardiovascular system. The coefficients of correlation of the latency of P300 with the amplitude
of mode of R-R intervals (AMo), index of tension in the regulatory systems by Baevskii (IT), and index of autonomic balance
by Baevskii (IAB) were 0.52 (P < 0.01), 0.36 (P < 0.05), and 0.37 (P < 0.05), respectively. The above autonomic indices demonstrated significant negative correlations with the volume of short-term
memory measured by Luriya’s test. The P300 latency, in turn, showed negative correlations with the memory volume estimated
by the MMSE scale and Luriya’s test. With increase in the age of patients, the degree of the above-mentioned correlations
between the P300 latency, memory volume (by Luriya’s test), and parameters of variational pulsometry increased. Our data emphasize
the expedience of “routine” studies of the balance of sympathetic and parasympathetic control in pathological states accompanied
by clear or subclinical cognitive disorders. Early recognition of cardiovascular dysfunction and its corresponding therapeutic
correction should improve the state of brain functions and quality of life in patients suffering from neurodegenerative diseases,
in particular from Parkinson’s disease.
Neirofiziologiya/Neurophysiology, Vol. 40, No. 1, pp. 43–52, January–February, 2008. 相似文献
6.
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
7.
Summary. The pathogenesis of several neurodegenerative diseases, including Alzheimer’s disease, has been linked to a condition of oxidative
and nitrosative stress, arising from the imbalance between increased reactive oxygen species (ROS) and reactive nitrogen species
(RNS) production and antioxidant defences or efficiency of repair or removal systems. The effects of free radicals are expressed
by the accumulation of oxidative damage to biomolecules: nucleic acids, lipids and proteins. In this review we focused our
attention on the large body of evidence of oxidative damage to protein in Alzheimer’s disease brain and peripheral cells as
well as in their role in signalling pathways. The progress in the understanding of the molecular alterations underlying Alzheimer’s
disease will be useful in developing successful preventive and therapeutic strategies, since available drugs can only temporarily
stabilize the disease, but are not able to block the neurodegenerative process. 相似文献
8.
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
9.
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
10.
Vella LJ Sharples RA Nisbet RM Cappai R Hill AF 《European biophysics journal : EBJ》2008,37(3):323-332
Exosomes are small membranous vesicles secreted by a number of cell types and can be isolated from conditioned cell media
or bodily fluids such as urine and plasma. Exosome biogenesis involves the inward budding of multivesicular bodies (MVB) to
form intraluminal vesicles (ILV). When fused with the plasma membrane, the MVB releases the vesicles into the extracellular
environment as exosomes. Proposed functions of these vesicles include roles in cell–cell signalling, removal of unwanted proteins,
and the transfer of pathogens between cells, such as HIV-1. Another such pathogen which exploits this pathway is the prion,
the infectious particle responsible for the transmissible neurodegenerative diseases such as Creutzfeldt-Jakob disease (CJD)
of humans or bovine spongiform encephalopathy (BSE) of cattle. Interestingly, this work is mirrored by studies on another
protein involved in neurodegenerative disease, the amyloid precursor protein (APP) which is associated with Alzheimer’s disease
(AD). Recent work has found APP proteolytic fragments in association with exosomes, suggesting a common pathway previously
unknown for proteins associated with neurodegenerative diseases. This review will be discussing the current literature regarding
the role of exosomes in secretion of the proteins, PrP and APP, and the subsequent implications for neurodegenerative disease.
Australian Society for Biophysics Special Issue: Metals and Membranes in Neuroscience. 相似文献
11.
Alzheimer’s disease is an irreversible, progressive neurodegenerative disorder leading invariably to death, usually within
7–10 years after diagnosis and is the leading cause of dementia in the elderly. Not only is Alzheimer’s disease a tragic disease
in which people suffer from neurodegeneration in the years to come, it also becomes an incredible burden on the public health
system. However, there is currently no effective treatment to halt the progression or prevent the onset of Alzheimer’s disease.
This is partly due to the fact that the complex pathophysiology of Alzheimer’s disease is not yet completely understood. Recently,
Golgi apparatus is found to play an important role in Alzheimer’s disease. In this review, we discuss the changes of Golgi
apparatus during clinical progression and pathological development of Alzheimer’s disease. First, changes of Golgi apparatus
size in Alzheimer’s disease are summarized. We then address the role of Golgi apparatus in the neuropathology of Alzheimer’s
disease. Finally, the role of Golgi apparatus in the pathogenesis of Alzheimer’s disease is discussed. Understanding the contribution
of Golgi apparatus dysfunction to Alzheimer’s disease and its pathophysiological basis will significantly impact our ability
to develop more effective therapies for Alzheimer’s disease. 相似文献
12.
Sagredo O García-Arencibia M de Lago E Finetti S Decio A Fernández-Ruiz J 《Molecular neurobiology》2007,36(1):82-91
Cannabinoids have been proposed as clinically promising neuroprotective molecules, as they are capable to reduce excitotoxicity,
calcium influx, and oxidative injury. They are also able to decrease inflammation by acting on glial processes that regulate
neuronal survival and to restore blood supply to injured area by reducing the vasoconstriction produced by several endothelium-derived
factors. Through one or more of these processes, cannabinoids may provide neuroprotection in different neurodegenerative disorders
including Parkinson’s disease and Huntington’s chorea, two chronic diseases that are originated as a consequence of the degeneration
of specific nuclei of basal ganglia, resulting in a deterioration of the control of movement. Both diseases have been still
scarcely explored at the clinical level for a possible application of cannabinoids to delay the progressive degeneration of
the basal ganglia. However, the preclinical evidence seems to be solid and promising. There are two key mechanisms involved
in the neuroprotection by cannabinoids in experimental models of these two disorders: first, a cannabinoid receptor-independent
mechanism aimed at producing a decrease in the oxidative injury and second, an induction/upregulation of cannabinoid CB2 receptors,
mainly in reactive microglia, that is capable to regulate the influence of these glial cells on neuronal homeostasis. Considering
the relevance of these preclinical data and the lack of efficient neuroprotective strategies in both disorders, we urge the
development of further studies that allow that the promising expectatives generated for these molecules progress from the
present preclinical evidence till a real clinical application. 相似文献
13.
Brain aging and the most diffused neurodegenerative diseases of the elderly are characterized by oxidative damage, redox metals
homeostasis impairment and inflammation. Food polyphenols can counteract these alterations in vitro and are therefore suggested
to have potential anti-aging and brain-protective activities, as also indicated by the results of some epidemiological studies.
Despite the huge and increasing amount of the in vitro studies trying to unravel the mechanisms of action of dietary polyphenols,
the research in this field is still incomplete, and questions about bioavailability, biotransformation, synergism with other
dietary factors, mechanisms of the antioxidant activity, risks inherent to their possible pro-oxidant activities are still
unanswered. Most of all, the capacity of the majority of these compounds to cross the blood–brain barrier and reach brain
is still unknown. This commentary discusses recent data on these aspects, particularly focusing on effects of curcumin, resveratrol
and catechins on Alzheimer’s disease.
Special issue article in honor of Dr. Anna Maria Giuffrida-Stella. 相似文献
14.
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
15.
16.
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
17.
Schapira AH 《Neurochemical research》2008,33(12):2502-2509
Mitochondria play a pivotal role in mammalian cell metabolism, hosting a number of important biochemical pathways including
oxidative phosphorylation. As might be expected from this fundamental contribution to cell function, abnormalities of mitochondrial
metabolism are a common cause of human disease. Primary mutations of mitochondrial DNA result in a diverse group of disorders
often collectively referred to as the mitochondrial encephalomyopathies. Perhaps more importantly in numerical terms are those
neurodegenerative diseases caused by mutations of nuclear genes encoding mitochondrial proteins. Finally there are mitochondrial
abnormalities induced by secondary events e.g. oxidative stress that may contribute to senescence, and environmental toxins
that may cause disease either alone or in combination with a genetic predisposition.
Special issue article in honor of Dr. Anna Maria Giuffrida-Stella. 相似文献
18.
Fesahat F Houshmand M Panahi MS Gharagozli K Mirzajani F 《Cellular and molecular neurobiology》2007,27(3):329-334
1. Alzheimer’s disease (AD) is the most common form of dementia in the elderly in which interplay between genes and the environment
is supposed to be involved. Mitochondrial DNA (mtDNA) has the only noncoding regions at the displacement loop (D-loop) region
that contains two hypervariable segments (HVS-I and HVS-II) with high polymorphism. mtDNA has already been fully sequenced
and many subsequent publications have shown polymorphic sites, haplogroups, and haplotypes. Haplogroups could have important
implications to understand the association between mutability of the mitochondrial genome and the disease.
2. To assess the relationship between mtDNA haplogroup and AD, we sequenced the mtDNA HVS-I in 30 AD patients and 100 control
subjects. We could find that haplogroups H and U are significantly more abundant in AD patients (P = 0.016 for haplogroup H and P = 0.0003 for haplogroup U), Thus, these two haplogroups might act synergistically to increase the penetrance of AD disease. 相似文献
19.
The importance of the role of the endocannabinoid system (ECS) in neurodegenerative diseases has grown during the past few
years. Mostly because of the high density and wide distribution of cannabinoid receptors of the CB1 type in the central nervous system (CNS), much research focused on the function(s) that these receptors might play in pathophysiological
conditions. Our current understanding, however, points to much diverse roles for this system. In particular, other elements
of the ECS, such as the fatty acid amide hydrolase (FAAH) or the CB2 cannabinoid receptor are now considered as promising pharmacological targets for some diseases and new cannabinoids have
been incorporated as therapeutic tools. Although still preliminary, recent reports suggest that the modulation of the ECS
may constitute a novel approach for the treatment of Alzheimer’s disease (AD). Data obtained in vitro, as well as in animal models for this disease and in human samples seem to corroborate the notion that the activation of
the ECS, through the use of agonists or by enhancing the endogenous cannabinoid tone, may induce beneficial effects on the
evolution of this disease. 相似文献
20.
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