共查询到20条相似文献,搜索用时 15 毫秒
1.
Paolo Calabresi Veronica Ghiglieri Petra Mazzocchetti Ilenia Corbelli Barbara Picconi 《Philosophical transactions of the Royal Society of London. Series B, Biological sciences》2015,370(1672)
The long-term replacement therapy with the dopamine (DA) precursor 3,4-dihydroxy-l-phenylalanine (L-DOPA) is a milestone in the treatment of Parkinson''s disease (PD). Although this drug precursor can be metabolized into the active neurotransmitter DA throughout the brain, its therapeutic benefit is due to restoring extracellular DA levels within the dorsal striatum, which lacks endogenous DA as a consequence of the neurodegenerative process induced by the disease. In the early phases of PD, L-DOPA treatment is able to restore both long-term depression (LTD) and long-term potentiation (LTP), two major forms of corticostriatal synaptic plasticity that are altered by dopaminergic denervation. However, unlike physiological DA transmission, this therapeutic approach in the advanced phase of the disease leads to abnormal peaks of DA, non-synaptically released, which are supposed to trigger behavioural sensitization, namely L-DOPA-induced dyskinesia. This condition is characterized by a loss of synaptic depotentiation, an inability to reverse previously induced LTP. In the advanced stages of PD, L-DOPA can also induce non-motor fluctuations with cognitive dysfunction and neuropsychiatric symptoms such as compulsive behaviours and impulse control disorders. Although the mechanisms underlying the role of L-DOPA in both motor and behavioural symptoms are still incompletely understood, recent data from electrophysiological and imaging studies have increased our understanding of the function of the brain areas involved and of the mechanisms implicated in both therapeutic and adverse actions of L-DOPA in PD patients. 相似文献
2.
Autophagy is an essential degradation pathway in clearing abnormal protein aggregates in mammalian cells and is responsible for protein homeostasis and neuronal health. Several studies have shown that autophagy deficits occurred in early stage of Alzheimer’s disease (AD). Autophagy plays an important role in generation and metabolism of β-amyloid (Aβ), assembling of tau and thus its malfunction may lead to the progress of AD. By considering the above evidences, autophagy may be a new target in developing drugs for AD. So far, a number of mammalian target of rapamycin (mTOR)-dependent and independent autophagy modulators have been identified to have positive effects in AD treatment. In this review, we summarized the latest progress supporting the role for autophagy deficits in AD and the potential therapeutic effects of autophagy modulators in AD. 相似文献
3.
Marzena Ułamek-Kozioł Wanda Furmaga-Jabłońska Sławomir Januszewski Judyta Brzozowska Małgorzata Ściślewska Mirosław Jabłoński Ryszard Pluta 《Neurochemical research》2013,38(9):1769-1773
Autophagy is a major intracellular degeneration pathway involved in the elimination and recycling of damaged organelles and long-lived proteins by lysosomes. Many of the pathological factors, which trigger neurodegenerative diseases, can perturb the autophagy activity, which is associated with misfolded protein aggregates accumulation in these disorders. Alzheimer’s disease, the first neurodegenerative disorder between dementias, is characterized by two aggregating proteins, β-amyloid peptide (plaques) and τ-protein (tangles). In Alzheimer’s disease autophagosomes dynamically form along neurites within neuronal cells and in synapses but effective clearance of these structures needs retrograde transportation towards the neuronal soma where there is a major concentration of lysosomes. Maturation of autophago-lysosomes and their retrograde trafficking are perturbed in Alzheimer’s disease, which causes a massive concentration of autophagy elements along degenerating neurites. Transportation system is disturbed along defected microtubules in Alzheimer’s disease brains. τ-protein has been found to control the stability of microtubules, however, phosphorylation of τ-protein or an increase in the total level of τ-protein can cause dysfunction of neuronal cells microtubules. Current evidence has shown that autophagy is developing in Alzheimer’s disease brains because of ineffective degradation of autophagosomes, which hold amyloid precursor protein-rich organelles and secretases important for β-amyloid peptides generation from amyloid precursor. The combination of raised autophagy induction and abnormal clearance of β-amyloid peptide-generating autophagic vacuoles creates circumstances helpful for β-amyloid peptide aggregation and accumulation in Alzheimer’s disease. However, the key role of autophagy in Alzheimer’s disease development is still under consideration today. One point of view suggests that abnormal autophagy induction causes a concentration of autophagic vacuoles rich in amyloid precursor protein, β-amyloid peptide and the elements crucial for its formation, whereas other hypothesis points to marred autophagic clearance or even decrease in autophagic effectiveness playing a role in maturation of Alzheimer’s disease. In this review we present the recent evidence linking autophagy to Alzheimer’s disease and the role of autophagic regulation in the development of full-blown Alzheimer’s disease. 相似文献
4.
5.
6.
7.
《Cell cycle (Georgetown, Tex.)》2013,12(3)
Comment on: Hou P, et al. Cell Cycle 2012; 11:286-95. 相似文献
8.
TREM2 in Alzheimer’s disease 总被引:1,自引:0,他引:1
Recent works have demonstrated a rare functional variant (R47H) in triggering receptor expressed on myeloid cells (TREM) 2 gene, encoding TREM2 protein, increase susceptibility to late-onset Alzheimer’s disease (AD), with an odds ratio similar to that of the apolipoprotein E ε4 allele. The reduced function of TREM2 was speculated to be the main cause in the pathogenic effects of this risk variant, and TREM2 is highly expressed in white matter, as well as in the hippocampus and neocortex, which is partly consistent with the pathological features reported in AD brain, indicating the possible involvement of TREM2 in AD pathogenesis. Emerging evidence has demonstrated that TREM2 could suppress inflammatory response by repression of microglia-mediated cytokine production and secretion, which may prevent inflammation-induced bystander damage of neurons. TREM2 also participates in the regulation of phagocytic pathways that are responsible for the removal of neuronal debris. In this article, we review the recent epidemiological findings of TREM2 that related with late-onset AD and speculate the possible roles of TREM2 in progression of this disease. Based on the potential protective actions of TREM2 in AD pathogenesis, targeting TREM2 might provide new opportunities for AD treatment. 相似文献
9.
Manasi P Jogalekar Anurag Veerabathini Prakash Gangadaran 《Experimental biology and medicine (Maywood, N.J.)》2021,246(15):1721
Since the worldwide emergence of the COVID-19 outbreak, there have been international concerns about the possible viral evolution into variants with underlying mutations that may contribute to their increased transmissibility, disease severity, risk of death, and their potential escape from the immune response or may even lead to its extinction. Rigorous surveillance has revealed the variants harboring mutations in the spike protein, the main target of neutralizing antibodies generated through vaccination or herd immunity. In this review, we have highlighted major SARS-CoV-2 variants as well as other local strains along with their specific mutations, suspected changes in their characteristics, and their impact on the current pandemic and vaccine efficacy. We have also emphasized the need to develop widely protective interventions to curb further transmission of variants. 相似文献
10.
Alzheimer’s disease (AD) is a devastating disease characterized by synaptic and neuronal loss in the elderly. Compelling evidence suggests that soluble amyloid-β peptide (Aβ) oligomers induce synaptic loss in AD. Aβ-induced synaptic dysfunction is dependent on overstimulation of N-methyl-D-aspartate receptors (NMDARs) resulting in aberrant activation of redox-mediated events as well as elevation of cytoplasmic Ca2+, which in turn triggers downstream pathways involving phospho-tau (p-tau), caspases, Cdk5/dynamin-related protein 1 (Drp1), calcineurin/PP2B, PP2A, Gsk-3β, Fyn, cofilin, and CaMKII and causes endocytosis of AMPA receptors (AMPARs) as well as NMDARs. Dysfunction in these pathways leads to mitochondrial dysfunction, bioenergetic compromise and consequent synaptic dysfunction and loss, impaired long-term potentiation (LTP), and cognitive decline. Evidence also suggests that Aβ may, at least in part, mediate these events by causing an aberrant rise in extrasynaptic glutamate levels by inhibiting glutamate uptake or triggering glutamate release from glial cells. Consequent extrasynaptic NMDAR (eNMDAR) overstimulation then results in synaptic dysfunction via the aforementioned pathways. Consistent with this model of Aβ-induced synaptic loss, Aβ synaptic toxicity can be partially ameliorated by the NMDAR antagonists (such as memantine and NitroMemantine). PSD-95, an important scaffolding protein that regulates synaptic distribution and activity of both NMDA and AMPA receptors, is also functionally disrupted by Aβ. PSD-95 dysregulation is likely an important intermediate step in the pathological cascade of events caused by Aβ. In summary, Aβ-induced synaptic dysfunction is a complicated process involving multiple pathways, components and biological events, and their underlying mechanisms, albeit as yet incompletely understood, may offer hope for new therapeutic avenues. 相似文献
11.
《生物化学与生物物理学报:癌评论》2019,1871(2):259-266
Necroptosis is a programmed, caspase-independent cell death that is morphologically similar to necrosis. Unlike apoptosis, necroptosis evokes inflammatory responses by releasing damage-associated molecular patterns. Recent studies suggest that tumor undergoes necroptosis in vivo and necroptosis has pro- or anti-tumoral effects in cancer development and progression. Furthermore, triggering necroptosis in tumor cells has been explored as a potential therapeutic strategy against cancer. Here, we will review the recent research progress of necroptosis in conferring anti- or pro-tumoral effects and its potential application in cancer therapy. 相似文献
12.
Chasing genes in Alzheimer’s and Parkinson’s disease 总被引:4,自引:0,他引:4
Alzheimers disease (AD), the most common type of dementia, and Parkinsons disease (PD), the most common movement disorder, are both neurodegenerative adult-onset diseases characterized by the progressive loss of specific neuronal populations and the accumulation of intraneuronal inclusions. The search for genetic and environmental factors that determine the fate of neurons during the ageing process has been a widespread approach in the battle against neurodegenerative disorders. Genetic studies of AD and PD initially focused on the search for genes involved in the aetiological mechanisms of monogenic forms of these diseases. They later expanded to study hundreds of patients, affected relative-pairs and population-based studies, sometimes performed on special isolated populations. A growing number of genes (and pathogenic mutations) is being identified that cause or increase susceptibility to AD and PD. This review discusses the way in which strategies of gene hunting have evolved during the last few years and the significance of finding genes such as the presenilins, -synuclein, parkin and DJ-1. In addition, we discuss possible links between these two neurodegenerative disorders. The clinical, pathological and genetic presentation of AD and PD suggests the involvement of a few overlapping interrelated pathways. Their imbricate features point to a spectrum of neurodegeneration (tauopathies, synucleinopathies, amyloidopathies) that need further intense investigation to find the missing links. 相似文献
13.
Alzheimer’s disease (AD) is the most common form of dementia. At the diagnostic stage, the AD brain is characterized by the accumulation of extracellular amyloid plaques, intracellular neurofibrillary tangles and neuronal loss. Despite the large variety of therapeutic approaches, this condition remains incurable, since at the time of clinical diagnosis, the brain has already suffered irreversible and extensive damage. In recent years, it has become evident that AD starts decades prior to its clinical presentation. In this regard, transgenic animal models can shed much light on the mechanisms underlying this “pre-clinical” stage, enabling the identification and validation of new therapeutic targets. This paper summarizes the formidable efforts to create models mimicking the various aspects of AD pathology in the rat. Transgenic rat models offer distinctive advantages over mice. Rats are physiologically, genetically and morphologically closer to humans. More importantly, the rat has a well-characterized, rich behavioral display. Consequently, rat models of AD should allow a more sophisticated and accurate assessment of the impact of pathology and novel therapeutics on cognitive outcomes. 相似文献
14.
Trinh Phuc N. H. Baltos Jo-Anne Hellyer Shane D. May Lauren T. Gregory Karen J. 《Purinergic signalling》2022,18(3):359-381
Purinergic Signalling - Alzheimer’s disease (AD) is the most common dementia in the elderly and its increasing prevalence presents treatment challenges. Despite a better understanding of the... 相似文献
15.
Tecalco-Cruz Angeles C. Zepeda–Cervantes Jesús Ortega-Domínguez Bibiana 《Molecular biology reports》2021,48(11):7517-7526
Molecular Biology Reports - Estrogens are hormones that play a critical role during development and growth for the adequate functioning of the reproductive system of women, as well as for... 相似文献
16.
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
17.
18.
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
19.
Autophagy is an essential and conserved lysosomal degradation pathway that controls the quality of cytoplasm by eliminating the intracellular aggregated proteins and damaged organelles. Autophagy works in mammalian target of rapamycin (mTOR)-dependent pathway or mTOR-independent pathway to keep the neuronal homeostasis. Mounting evidence has implicated the importance of defective autophagy in the pathogenesis of aging and neurodegenerative diseases, especially in Alzheimer’s disease (AD). It has also demonstrated a neuroprotective role of autophagy in mediating the degradation of amyloid beta and tau which are major factors of AD. Amounts of molecules function in either mTOR-dependent pathway or mTOR-independent pathway to induce autophagy, which maybe a potential treatment for AD. In this review, we summarize the latest studies concerning the role of autophagy in AD and explore autophagy modulation as a potential therapeutic strategy for AD. However, to date, little of the researches on autophagy have been performed to investigate the modulation in AD; more investigations need to be confirmed in the future. 相似文献
20.
Danni Li Fangying Huang Yingchun Zhao Peter W. Villata Timothy J. Griffin Lin Zhang Ling Li Fang Yu 《Clinical proteomics》2018,15(1):31