共查询到20条相似文献,搜索用时 15 毫秒
1.
Caroline Van Cauwenberghe Charysse Vandendriessche Claude Libert Roosmarijn E. Vandenbroucke 《Mammalian genome》2016,27(7-8):300-319
Dietary interventions such as caloric restriction (CR) extend lifespan and health span. Recent data from animal and human studies indicate that CR slows down the aging process, benefits general health, and improves memory performance. Caloric restriction also retards and slows down the progression of different age-related diseases, such as Alzheimer’s disease. However, the specific molecular basis of these effects remains unclear. A better understanding of the pathways underlying these effects could pave the way to novel preventive or therapeutic strategies. In this review, we will discuss the mechanisms and effects of CR on aging and Alzheimer’s disease. A potential alternative to CR as a lifestyle modification is the use of CR mimetics. These compounds mimic the biochemical and functional effects of CR without the need to reduce energy intake. We discuss the effect of two of the most investigated mimetics, resveratrol and rapamycin, on aging and their potential as Alzheimer’s disease therapeutics. However, additional research will be needed to determine the safety, efficacy, and usability of CR and its mimetics before a general recommendation can be proposed to implement them. 相似文献
2.
《Trends in molecular medicine》2023,29(8):659-672
Progression of Alzheimer’s disease (AD) entails deterioration or aberrant function of multiple brain cell types, eventually leading to neurodegeneration and cognitive decline. Defining how complex cell–cell interactions become dysregulated in AD requires novel human cell-based in vitro platforms that could recapitulate the intricate cytoarchitecture and cell diversity of the human brain. Brain organoids (BOs) are 3D self-organizing tissues that partially resemble the human brain architecture and can recapitulate AD-relevant pathology. In this review, we highlight the versatile applications of different types of BOs to model AD pathogenesis, including amyloid-β and tau aggregation, neuroinflammation, myelin breakdown, vascular dysfunction, and other phenotypes, as well as to accelerate therapeutic development for AD. 相似文献
3.
Alzheimer’s disease (AD) is by far the most common dementing illness of late life and is increasing with the ever-growing number of older adults, in particular, in developed countries. The disease is often referred to as the “Long-Goodbye” because the person with the illness slowly becomes lost to everyone a long time before the body finally gives out. Being able to detect AD earlier on during the course of the disease offers better prospects for the future, for AD individuals, their families and friends as well as on the economy, as a whole. Unfortunately, such a detection technique is not yet, available. However, there are a number of promising biological markers (biomarkers) that correlate well with clinical cognitive tests of individuals and/or postmortem histopathological manifestations of the disease, especially when at least two markers are used for the diagnosis. Biosensors are tools that combine a biochemical binding element to a signal conversion unit and are already being used in the study of some AD biomarkers. However, their use in clinical diagnosis remains a challenge. Introduction of nanotechnology leading to nanobiosensors has several potential advantages over other clinical and/or existing analytical tools, including increased assay speed, flexibility, reduced cost of diagnostic testing, potential to deliver molecular diagnostic tools to family general practitioners, and other health care systems. Even more important, nano-based assays have the potential to detect target proteins at attomolar concentration level. They are, therefore, being increasingly exploited for the detection of early metabolic changes associated with diseases. Because brain damage is irreversible, the use of nanotechnology is particularly important in AD and other neurodegenerative disorders. Nanosensors can also facilitate and enable pointofcare-testing (POCT). This article reviews the basic biochemical processes that lead to AD pathology, current biomarkers for AD, and the current role of nanosensor technology for the study of AD biomarkers. Furthermore, it discusses the huge potential of nanosensing to deliver new molecular diagnostic strategies to AD research. 相似文献
4.
Sian-Yang Ow Dave E Dunstan 《Protein science : a publication of the Protein Society》2014,23(10):1315-1331
Amyloid fibrils are self-assembled fibrous protein aggregates that are associated with a number of presently incurable diseases such as Alzheimer’s and Parkinson’s disease. Millions of people worldwide suffer from amyloid diseases. This review summarizes the unique cross-β structure of amyloid fibrils, morphological variations, the kinetics of amyloid fibril formation, and the cytotoxic effects of these fibrils and oligomers. Alzheimer’s disease is also explored as an example of an amyloid disease to show the various approaches to treat these amyloid diseases. Finally, this review investigates the nanotechnological and biological applications of amyloid fibrils; as well as a summary of the typical biological pathways involved in the disposal of amyloid fibrils and their precursors. 相似文献
5.
Life expectancy has increased in most developed countries, which has led to an increase in the proportion of elderly people in the world’s population. However, this increase in life expectancy is not accompanied by a lengthening of the health span since aging is characterized with progressive deterioration in cellular and organ functions. The brain is particularly vulnerable to disease, and this is reflected in the onset of age-related neurodegenerative diseases such as Alzheimer’s disease. Research shows that dysfunction of two barriers in the central nervous system (CNS), the blood–brain barrier (BBB) and the blood–cerebrospinal fluid (CSF) barrier (BCSFB), plays an important role in the progression of these neurodegenerative diseases. The BBB is formed by the endothelial cells of the blood capillaries, whereas the BCSFB is formed by the epithelial cells of the choroid plexus (CP), both of which are affected during aging. Here, we give an overview of how these barriers undergo changes during aging and in Alzheimer’s disease, thereby disturbing brain homeostasis. Studying these changes is needed in order to gain a better understanding of the mechanisms of aging at the brain barriers, which might lead to the development of new therapies to lengthen the health span (including mental health) and reduce the chances of developing Alzheimer’s disease. 相似文献
6.
Alzheimer??s disease (AD) is a serious neurodegenerative disorder and its cause remains largely elusive. In past years, genome-wide association (GWA) studies have provided an effective means for AD research. However, the univariate method that is commonly used in GWA studies cannot effectively detect the biological mechanisms associated with this disease. In this study, we propose a new strategy for the GWA analysis of AD that combines random forests with enrichment analysis. First, backward feature selection using random forests was performed on a GWA dataset of AD patients carrying the apolipoprotein gene (APOE?4) and 1058 susceptible single nucleotide polymorphisms (SNPs) were detected, including several known AD-associated SNPs. Next, the susceptible SNPs were investigated by enrichment analysis and significantly-associated gene functional annotations, such as ??alternative splicing??, ??glycoprotein??, and ??neuron development??, were successfully discovered, indicating that these biological mechanisms play important roles in the development of AD in APOE?4 carriers. These findings may provide insights into the pathogenesis of AD and helpful guidance for further studies. Furthermore, this strategy can easily be modified and applied to GWA studies of other complex diseases. 相似文献
7.
The FK506-binding protein (FKBP) family of immunophilins consists of proteins with a variety of protein–protein interaction
domains and versatile cellular functions. Analysis of the functions of immunophilins has been the focus of studies in recent
years and has led to the identification of various molecular pathways in which FKBPs play an active role. All FKBPs contain
a domain with prolyl cis/trans isomerase (PPIase) activity. Binding of the immunosuppressant molecule FK506 to this domain inhibits their PPIase activity
while mediating immune suppression through inhibition of calcineurin. The larger members, FKBP51 and FKBP52, interact with
Hsp90 and exhibit chaperone activity that is shown to regulate steroid hormone signalling. From these studies it is clear
that FKBP proteins are expressed ubiquitously but show relatively high levels of expression in the nervous system. Consistent
with this expression, FKBPs have been implicated with both neuroprotection and neurodegeneration. This review will focus on
recent studies involving FKBP immunophilins in Alzheimer’s-disease-related pathways. 相似文献
8.
E. E. Dubinina L. V. Schedrina N. G. Neznanov N. M. Zalutskaya D. V. Zakharchenko 《Biochemistry (Moscow) Supplemental Series B: Biomedical Chemistry》2014,8(3):181-191
The review summarizes literature data on the importance of oxidative stress as one of the pathogenetic mechanisms in Alzheimer’s disease. Special attention is paid to the main specific and nonspecific ways of reactive oxygen species (ROS) generation in the course of the disease development. Generated ROS influence functional activity of cells, particularly, apoptosis and the mitotic cycle. Phosphorylation/dephosphorylation processes associated with intense phosphorylation of tau protein and mitosis-specific proteins play the nodal regulatory role in the cell. Alzheimer’s disease is accompanied by impairments of the regulatory functions of peptidyl-prolyl isomerases, particularly, Pin1 involved in maintaining a balanced state of phosphorylation/dephosphorylation processes. Taking into consideration the multifactorial impairment of the cell cycle control, this process should be considered from the viewpoint of the general state of metabolic processes, and oxidative stress has one of the key positions in aging. 相似文献
9.
Our ageing society is confronted with a dramatic increase in incidence of age-related neurodegenerative diseases; biomedical research leading to novel therapeutic strategies is crucial to address this problem. Animal models of neurodegenerative conditions are invaluable in improving our understanding of the molecular basis of pathology, potentially revealing novel targets for intervention. Here, we review transgenic animal models of Alzheimer’s and Parkinson’s disease reported in mice, zebrafish, Caenorhabditis elegans and Drosophila melanogaster. This information will enable researchers to compare different animal models targeting disease-associated molecules by genomic engineering and to facilitate the development of novel animal models for any particular study, depending on the ultimate research goals. 相似文献
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11.
《朊病毒》2013,7(5-6):261-265
ABSTRACTThe recent Research Framework proposed by the US National Institute on Aging and the Alzheimer’s Association (NIA-AA) recommends that Alzheimer’s disease be defined by its specific biology rather than by non-specific neurodegenerative and syndromal features. By affirming markers of abnormal Aβ and tau proteins as the essential pathobiological signature of Alzheimer’s disease, the Framework tacitly reinforces the amyloid (Aβ) cascade as the leading theory of Alzheimer pathogenesis. In light of recent evidence that the cascade is driven by the misfolding and templated aggregation of Aβ and tau, we believe that an empirically grounded Standard Model of Alzheimer’s pathogenesis is within reach. A Standard Model can clarify and consolidate existing information, contextualize risk factors and the complex disease phenotype, identify testable hypotheses for future research, and pave the most direct path to effective prevention and treatment. 相似文献
12.
Background
Alzheimer disease (AD) is a progressive neurodegenerative disease that destroys memory and cognitive skills. AD is characterized by the presence of two types of neuropathological hallmarks: extracellular plaques consisting of amyloid β-peptides and intracellular neurofibrillary tangles of hyperphosphorylated tau proteins. The disease affects 5 million people in the United States and 44 million world-wide. Currently there is no drug that can cure, stop or even slow the progression of the disease. If no cure is found, by 2050 the number of alzheimer’s patients in the U.S. will reach 15 million and the cost of caring for them will exceed $ 1 trillion annually.Results
The present paper develops a mathematical model of AD that includes neurons, astrocytes, microglias and peripheral macrophages, as well as amyloid β aggregation and hyperphosphorylated tau proteins. The model is represented by a system of partial differential equations. The model is used to simulate the effect of drugs that either failed in clinical trials, or are currently in clinical trials.Conclusions
Based on these simulations it is suggested that combined therapy with TNF- α inhibitor and anti amyloid β could yield significant efficacy in slowing the progression of AD.13.
Youngjae Jeon Soojin Lee Myoungchul Shin Jang Ho Lee Yoon Seok Suh Soojin Hwang 《Animal cells and systems.》2017,21(3):160-168
Drosophila melanogaster expressing amyloid-β42 (Aβ42) transgenes have been used as models to study Alzheimer’s disease. Various Aβ42 transgenes with different structures induce different phenotypes, which make it difficult to compare data among studies which use different transgenic lines. In this study, we compared the phenotypes of four frequently used Aβ42 transgenic lines, UAS-Aβ422X, UAS-Aβ42BL33770, UAS-Aβ4211C39, and UAS-Aβ42H29.3. Among the four transgenic lines, only UAS-Aβ422X has two copies of the upstream activation sequence-amyloid-β42 (UAS-Aβ42) transgene, while remaining three have one copy. UAS-Aβ42BL33770 has the 3′ untranslated region of Drosophila α-tubulin, while the others have that of SV40. UAS-Aβ4211C39 and UAS-Aβ42H29.3 have the rat pre-proenkephalin signal peptide, while UAS-Aβ422X and UAS-Aβ42BL33770 have that of the fly argos protein. When the transgenes were expressed ectopically in the developing eyes of the flies, UAS-Aβ422X transgene resulted in a strongly reduced and rough eye phenotype, while UAS-Aβ42BL33770 only showed a strong rough eye phenotype; UAS-Aβ42H29.3 and UAS-Aβ4211C39 had mild rough eyes. The levels of cell death and reactive oxygen species (ROS) in the eye imaginal discs were consistently the highest in UAS-Aβ422X, followed by UAS-Aβ42BL33770, UAS-Aβ4211C39, and UAS-Aβ42H29.3. Surprisingly, the reduction in survival during the development of these lines did not correlate with cell death or ROS levels. The flies which expressed UAS-Aβ4211C39 or UAS-Aβ42H29.3 experienced greatly reduced survival rates, although low levels of ROS or cell death were detected. Collectively, our results demonstrated that different Drosophila AD models show different phenotypic severity, and suggested that different transgenes may have different modes of cytotoxicity.
Abbreviations: Aβ42: amyloid-β42; AD: Alzheimer’s disease; UAS: upstream activation sequence 相似文献
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Alzheimer’s disease (AD) is a most common neurodegenerative disorder, which associates with impaired cognition. Gut microbiota can modulate host brain function and behavior via microbiota-gut-brain axis, including cognitive behavior. Germ-free animals, antibiotics, probiotics intervention and diet can induce alterations of gut microbiota and gut physiology and also host cognitive behavior, increasing or decreasing risks of AD. The increased permeability of intestine and blood-brain barrier induced by gut microbiota disturbance will increase the incidence of neurodegeneration disorders. Gut microbial metabolites and their effects on host neurochemical changes may increase or decrease the risk of AD. Pathogenic microbes infection will also increase the risk of AD, and meanwhile, the onset of AD support the “hygiene hypothesis”. All the results suggest that AD may begin in the gut, and is closely related to the imbalance of gut microbiota. Modulation of gut microbiota through personalized diet or beneficial microbiota intervention will probably become a new treatment for AD. 相似文献
16.
Macreadie IG 《European biophysics journal : EBJ》2008,37(3):295-300
This brief review discusses copper transport in humans, with an emphasis on knowledge learned from one of the simplest model
organisms, yeast. There is a further focus on copper transport in Alzheimer’s Disease (AD). Copper homeostasis is essential
for the well-being of all organisms, from bacteria to yeast to humans: survival depends on maintaining the required supply
of copper for the many enzymes, dependent on copper for activity, while ensuring that there is no excess free copper, which
would cause toxicity. A virtual orchestra of proteins are required to achieve copper homeostasis. For copper uptake, Cu(II)
is first reduced to Cu(I) via a membrane-bound reductase. The reduced copper can then be internalised by a copper transporter
where it is transferred to copper chaperones for transport and specific delivery to various organelles. Of significance are
internal copper transporters, ATP7A and ATP7B, notable for their role in disorders of copper deficiency and toxicity, Menkes
and Wilson’s disease, respectively. Metallothioneins and Cu/Zn superoxide dismutase can protect against excess copper in cells.
It is clear too, increasing age, environmental and lifestyle factors impact on brain copper. Studies on AD suggest an important
role for copper in the brain, with some AD therapies focusing on mobilising copper in AD brains. The transport of copper into
the brain is complex and involves numerous players, including amyloid precursor protein, Aβ peptide and cholesterol. 相似文献
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18.
Liu He Ashley Boice Kai Liu Xing Yan Yuqi Jiang Shijun Zhang 《Bioorganic & medicinal chemistry letters》2018,28(6):1030-1036
In our continuing efforts to develop bivalent compounds as potential neuroprotectants for Alzheimer’s disease, a series of bivalent compounds that contain cholesterylamine and an extended spacer were synthesized and biologically characterized. Our results demonstrated that incorporation of a piperazine ring into the spacer composition significantly improved the protective potency in MC65 cell models. Our results also suggested that the optimal spacer length for such bivalent compounds ranges from 17 to 21 atoms, and further spacer extension beyond 21 atoms results no further optimization. Notably, incorporation of a piperazine ring into the spacer diminished the biometal chelating capacity for these bivalent compounds, thus suggesting structural flexibility of these compounds in interactions with metals. Collectively, the results provided valuable guidance to develop new bivalent compounds as neuroprotectants for Alzheimer’s disease. 相似文献
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Danni Li Fangying Huang Yingchun Zhao Peter W. Villata Timothy J. Griffin Lin Zhang Ling Li Fang Yu 《Clinical proteomics》2018,15(1):31