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1.
Peter L. Pedersen 《Journal of bioenergetics and biomembranes》2009,41(5):403-405
In recent years mitochondria, as the most abundant organelles in animal and human cells, have come to the forefront of biomedical
research as they are now recognized not only as the major producers of ATP needed to drive cellular functions critical for
life, but they are also the instruments of cell death. Not surprisingly, therefore, mitochondria are now known to be involved
in many different diseases ranging from those that affect millions worldwide to those that affect only a few, i.e., rare diseases.
These diseases include in addition to cardio-myopathies and cancer also diseases that affect many other organs/tissues including
the brain/nervous system, the latter diseases now commonly referred to as “neurodegenerative diseases”. Specifically, the
subject of this mini-review series focuses on the role of mitochondria in Alzheimer’s disease, a major age related neurodegenerative
disease that results in loss or decline of memory and other cognitive abilities. This devastating disease affects millions
of Americans, and globally multi-millions with very grim predictions for the future. Although the molecular and gene-related
details that underlie Alzheimer’s disease remain to be clearly elucidated, mitochondria appear to be very intimately involved.
The purpose of this mini-review series is to summarize how various investigators working on this subject envision the role(s)
of mitochondria in Alzheimer’s disease. The development of future therapies for this disease is likely to rely heavily on
the new knowledge gained. 相似文献
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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
4.
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
5.
The accumulation of intracellular protein deposits as inclusion bodies is the common pathological hallmark of most age related
neurodegenerative disorders including polyglutamine diseases. Appearances of aggregates of the misfolded mutant disease proteins
suggest that the cells are unable to efficiently degrade them, and failure of clearance leads to the severe disturbances of
the cellular quality control system. The quality control ubiquitin ligases are now increasingly implicated in the biology
of polyglutamine diseases, Parkinson’s diseases, Amyotrophic lateral sclerosis and Alzheimer’s disease. Here we review the recent studies that have revealed a critical role of E3 ubiquitin ligases in understanding the
pathogenesis of polyglutamine diseases. 相似文献
6.
The importance of microRNAs as key molecular components of cellular processes is now being recognized. Recent reports have shown that microRNAs regulate processes as diverse as protein expression and nuclear functions inside cells and are able to signal extracellularly, delivered via exosomes, to influence cell fate at a distance. The versatility of microRNAs as molecular tools inspires the design of novel strategies to control gene expression, protein stability, DNA repair and chromatin accessibility that may prove very useful for therapeutic approaches due to the extensive manageability of these small molecules. However, we still lack a comprehensive understanding of the microRNA network and its interactions with the other layers of regulatory elements in cellular and extracellular functions. This knowledge may be necessary before we exploit microRNA versatility in therapeutic settings. To identify rules of interactions between microRNAs and other regulatory systems, we begin by reviewing microRNA activities in a single cell type: the melanocyte, from development to disease. 相似文献
7.
Chronic gastro-oesophageal reflux disease can induce a metaplastic change of the distal oesophagus called Barrett’s oesophagus
whereby the normal squamous epithelium is substituted by a columnar epithelium. Patients with Barrett’s oesophagus are at
increased risk of oesophageal adenocarcinoma which occurs through dysplastic stages with increasing degree of cellular and
architectural disorganization. Barrett’s oesophagus represents an ideal model to study the genetic events supporting the onset
of an invasive tumour since patients with this condition are surveilled with endoscopic tissue sampling until high grade dysplasia
or intramucosal carcinoma develop. However, due to the relatively low incidence of this disease compared to other cancers,
i.e. colon and breast, it is only recently that researchers have concentrated on understanding the genetic events supporting
the onset of Barrett’s and its transformation to cancer. Here, we review the knowledge acquired so far on the genetic and
molecular alterations along the oesophageal metaplasia–dysplasia-carcinoma sequence. 相似文献
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Alzheimer’s disease is a progressive neurodegenerative disorder that affects primarily learning and memory functions. There
is significant neuronal loss and impairment of metabolic functioning in the temporal lobe, an area believed to be crucial
for learning and memory tasks. Aggregated deposits of amyloid β-peptide may have a causative role in the development and progression
of AD. We review the cellular actions of Aβ and how they can contribute to the cytotoxicity observed in AD. Aβ causes plasma
membrane lipid peroxidation, impairment of ionmotive ATPases, glutamate uptake, uncoupling of a G-protein linked receptor,
and generation of reactive oxygen species. These effects contribute to the loss of intracellular calcium homeostasis reported
in cultured neurons. Many cell types other than neurons show alterations in the Alzheimer’s brain. The effects of Aβ on these
cell types is also reviewed. 相似文献
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Wilson’s disease is an autosomal recessive disorder of copper accumulation in various organs, with most common clinical manifestations
such as hepatic, neurological, and renal dysfunctions. Serum copper and ceruloplasmin in Wilson’s disease were significantly
lower as compared to normals, controls, and relatives of Wilson’s disease patients, whereas marked hypercupriuria (145 ± 7
μg/24 h) was observed in Wilson’s children only. A good correlation (r = 0.92) was found between non-ceruloplasmin-bound copper and 24-h urinary copper excretion in Wilson’s disease patients.
Further, copper studies among the different phenotypes of Wilson’s disease revealed substantially low serum ceruloplasmin
and a marked hypercupriuria in Wilson’s disease children associated with renal tubular acidosis as compared to the patients
with either hepatological or neurological manifestations. Serum ceruloplasmin levels in 14 patients of Wilson’s disease were
between 14 and 20 mg/dL. These patients of Wilson’s disease were confirmed by measuring liver biopsy copper, which was about
nine times higher than normal hepatic copper content. During the family screening by copper studies, four asymptomatic siblings
were diagnosed for Wilson’s disease. These subjects were then started on D-penicillamine therapy because presymptomatic treatment
prevents progression of the disease complications. 相似文献
12.
Transgenic systems are widely used to study the cellular and molecular basis of human neurodegenerative diseases. A wide variety
of model organisms have been utilized, including bacteria (Escherichia coli), plants (Arabidopsis thaliana), nematodes (Caenorhabditis elegans), arthropods (Drosophila melanogaster), fish (zebrafish, Danio rerio), rodents (mouse, Mus musculus and rat, Rattus norvegicus) as well as non-human primates (rhesus monkey, Macaca mulatta). These transgenic systems have enormous value for understanding the pathophysiological basis of these disorders and have,
in some cases, been instrumental in the development of therapeutic approaches to treat these conditions. In this review, we
discuss the most commonly used model organisms and the methodologies available for the preparation of transgenic organisms.
Moreover, we provide selected examples of the use of these technologies for the preparation of transgenic animal models of
neurodegenerative diseases, including Alzheimer’s disease (AD), frontotemporal lobar degeneration (FTLD), amyotrophic lateral
sclerosis (ALS), Huntington’s disease (HD) and Parkinson’s disease (PD) and discuss the application of these technologies
to AD as an example of how transgenic modeling has affected the study of human neurodegenerative diseases. 相似文献
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14.
Protein conformational diseases arise when a cellular protein adopts an aberrant shape that either directly or indirectly
alters the physiology of its host cell. Notable conformational diseases include cystic fibrosis, Huntington’s disease, the
prion-related diseases, Alzheimer’s disease, and antitrypsin deficiency. In principle, the severity and progression of conformational
diseases can be altered by cellular factors that recognize and attempt to ameliorate the harmful effects of the disease-causing,
misshapen protein. To better define the mechanistic underpinnings of cellular factors that mediate quality control, and to
understand why a single misfolded protein can impact cell viability, specific proteins that cause each of the diseases listed
above have been expressed in a model eukaryote, the yeast Saccharomyces cerevisiae. In this review, we describe what has been learned from these studies, and speculate on future uses of yeast expression systems. 相似文献
15.
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
16.
Ferrando-Miguel R Rosner M Freilinger A Lubec G Hengstschläger M 《Neurochemical research》2005,30(11):1413-1419
Tuberous sclerosis complex (TSC) is a common genetic disorder in which affected individuals develop mental retardation, developmental
brain defects and seizures. The TSC gene products, hamartin and tuberin, form a complex, of which tuberin is assumed to be
the functional component being involved in a wide variety of different cellular processes. Here we report that tuberin protein
levels are decreased in the frontal cortex of patients with Alzheimer’s disease. In addition, tuberin levels are also decreased
in Down syndrome brain samples positive for β-amyloid plaques and neurofibrillary tangles. Analysis of NeuN revealed that
this regulation is not a consequence of differences in the amount of postmitotic neurons. This first connection of tuberin
to another common disease beside TSC stimulates new approaches to investigate the molecular development and to establish new
therapeutic strategies. 相似文献
17.
B. Borisch Chappuis H. Müller J. Stutte M. M. Hey K. Hübner H. K. Müller-Hermelink 《Virchows Archiv. B, Cell pathology including molecular pathology》1989,58(1):199-205
Fourteen examples of non-Hodgkin’s lymphoma (NHL) and four of Hodgkin’s disease in patients with AIDS as well as lymph nodes
exhibiting changes related to the lymphadenopathy syndrome (LAS) from 11 HIV-positive individuals were studied for the presence
of Epstein-Barr virus (EBV) genome both by in situ DNA hybridization and blotting techniques. Both methods were performed
using formalin-fixed paraffin-embedded material. All the NHLs were of high malignancy and all but one were of the B-cell type.
Of the four examples of Hodgkin’s disease, two were lymphocytic predominant, one of mixed cellularity and one of the nodular
sclerosing variety. The lymph nodes of patients with LAS were mostly stage I with marked follicular hyperplasia. In 7 of the
14 NHLs the presence of EBV-DNA was clearly demonstrated by dot-blotting and by in situ hybridization. All lymph nodes from
the patients with LAS and AIDS-related Hodgkin’s disease were negative for EBV by dot-blot and in situ hybridization assays.
We conclude that EBV plays a role in the development of AIDS-related lymphomas, but the fact that half these lymphomas are
EBV-negative suggests that other mechanisms such as polyclonal stimulation of B-cells by HIV products may also be important.
This study was supported by the DFG, SFB 172 to BBC and HKMH and by the BMFT grant 01KI 88061 to BBC 相似文献
18.
Stem cells and neurodegenerative diseases 总被引:1,自引:0,他引:1
Neurodegenerative diseases are characterized by the neurodegenerative changes or apoptosis of neurons involved in networks, which are important to specific physiological functions. With the de-velopment of old-aging society, the incidence of neurodegenerative diseases is on the increase. How-ever, it is difficult to diagnose for most of neurodegenerative diseases. At present, there are too few effective therapies. Advances in stem cell biology have raised the hope and possibility for the therapy of neurodegenerative diseases. Recently, stem cells have been widely attempted to treat neurodegen-erative diseases of animal model. Here we review the progress and prospects of various stem cells, including embryonic stem cells, mesenchymal stem cell and neural stem cells and so on, for the treatments of neurodegenerative diseases, such as Parkinson’s disease, Alzheimer’s disease, Hunt-ington’s disease and Amyotrophic lateral sclerosis/Lou Gehrig’s disease. 相似文献
19.
Zhu X Lee HG Casadesus G Avila J Drew K Perry G Smith MA 《Molecular neurobiology》2005,31(1-3):205-217
Oxidative stress is a striking feature of susceptible neurons in the Alzheimer’s disease brain. Importantly, because oxidative
stress is an early event in Alzheimer’s disease, proximal to the development of hallmark pathologies, it likely plays an important
role in the pathogenesis of the disease. Investigations into the cause of such oxidative stress show that interactions between
abnormal mitochondria and disturbed metal metabolism are, at least in part, responsible for cytoplasmic oxidative damage observed
in these susceptible neurons, which could ultimately lead to their demise. Oxidative stress not only temporally precedes the
pathological lesions of the disease but could also contribute to their formation, which, in turn, could provide some protective
mechanism to reduce oxidative stress and ensure that neurons do not rapidly succumb to oxidative insults. In this review,
we present the evidence for oxidative stress in Alzheimer’s disease and its likely sources and consequence in relation to
other pathological changes. 相似文献
20.
Summary. The accumulation of oxidized proteins is known to be linked to some severe neurodegenerative diseases like Alzheimer’s, Parkinson’s
and Huntington’s disease. Furthermore, the aging process is also accompanied by an ongoing aggregation of misfolded and damaged
proteins. Therefore, mammalian cells have developed potent degradation systems, which selectively degrade damaged and misfolded
proteins. The proteasomal system is largely responsible for the removal of oxidatively damaged proteins form the cellular
environment. Not only cytosolic proteins are prone to oxidative stress, also nuclear proteins are readily oxidized. The nuclear
proteasomal system is responsible for the degradation of these proteins. This review is focused on the specific degradation
of oxidized nuclear proteins, the role of the proteasome in this process and the regulation of the nuclear proteasomal system
under oxidative conditions. 相似文献