1,721,020 research outputs found
Aberrant protein networks in Alzheimer disease
No full textUse of a proteomics approach has demonstrated that changes in protein expression association with Alzheimer disease are not always reflected in changes in RNA levels, highlighting the importance of directly studying proteomic changes to a full understanding of Alzheimer disease pathogenesis
Redox imbalance and metabolic defects in the context of Alzheimer disease
No full textRedox reactions play a critical role for intracellular processes, including path- ways involved in metabolism and signaling. Reactive oxygen species (ROS) act either as second messengers or generators of protein modifications, funda- mental mechanisms for signal transduction. Disturbance of redox homeostasis is associated with many disorders. Among these, Alzheimer’s disease is a neu- rodegenerative pathology that presents hallmarks of oxidative damage such as increased ROS production, decreased activity of antioxidant enzymes, oxi- dative modifications of macromolecules, and changes in mitochondrial homeo- stasis. Interestingly, alteration of redox homeostasis is closely associated with defects of energy metabolism, involving both carbohydrates and lipids, the major energy fuels for the cell. As the brain relies exclusively on glucose metabolism, defects of glucose utilization represent a harmful event for the brain. During aging, a progressive perturbation of energy metabolism occurs resulting in brain hypometabolism. This condition contributes to increase neu- ronal cell vulnerability ultimately resulting in cognitive impairment. The cur- rent review discusses the crosstalk between alteration of redox homeostasis and brain energy defects that seems to act in concert in promoting Alzhei- mer’s neurodegeneration
From redox proteomics to clinical practice: Search for therapeutic targets
No full textAlzheimer disease (AD) is the most common form of dementia in the elderly population, characterized by a gradual deterioration of memory and other cognitive functions. The major pathological characteristics of AD brains are the presence of senile plaques, made of amyloid β-peptide (Aβ), neurofibrillary tangles, composed of hyperphosphorylated tau protein, and neuronal loss. Among putative mechanisms responsible of neurodegeneration, several studies demonstrated the role of oxidative stress as an important factor contributing to the initiation and progression of AD. If from one side disruption of redox balance and increased production of free radicals are likely to be related to mitochondria dysfunction and/or aberrant accumulation of misfolded proteins, on the other side the abnormal accumulation of Aβ and tau proteins appears to promote the redox imbalance. In addition, evidence has suggested that oxidative stress may augment the production and aggregation of Aβ and facilitate the phosphorylation and polymerization of tau, thus forming a vicious cycle that promotes the initiation and progression of AD. Taken together, these findings suggest that therapeutic strategies aimed at preventing/reducing oxidative stress-mediated damage may be effective for the treatment of AD and other neurodegenerative disorders
Targeting mitochondria in Alzheimer disease: rationale and perspectives
Full text linkA decline in mitochondrial function plays a key role in the aging process and increases the incidence of age-related disorders, including Alzheimer disease (AD). Mitochondria—the power station of the organism—can affect several different cellular activities, including abnormal cellular energy generation, response to toxic insults, regulation of metabolism, and execution of cell death. In AD subjects, mitochondria are characterized by impaired function such as lowered oxidative phosphorylation, decreased adenosine triphosphate production, significant increased reactive oxygen species generation, and compromised antioxidant defense. The current review discusses the most relevant mitochondrial defects that are considered to play a significant role in AD and that may offer promising therapeutic targets for the treatment/prevention of AD. In addition, we discuss mechanisms of action and translational potential of some promising mitochondrial and bioenergetic therapeutics for AD including compounds able to potentiate energy production, antioxidants to scavenge reactive oxygen species and reduce oxidative damage, glucose metabolism, and candidates that target mitophagy. While mitochondrial therapeutic strategies have shown promise at the preclinical stage, there has been little progress in clinical trials. Thus, there is an urgent need to better understand the mechanisms regulating mitochondrial homeostasis in order to identify powerful drug candidates that target ‘in and out’ the mitochondria to preserve cognitive functions
The interplay among oxidative stress, brain insulin resistance and AMPK dysfunction contribute to neurodegeneration in type 2 diabetes and Alzheimer disease
No full textAlzheimer's disease (AD) is the most common form of dementia in the elderly followed by vascular dementia. In addition to clinically diagnosed dementia, cognitive dysfunction has been reported in diabetic patients. Recent studies are now beginning to recognize type 2 diabetes mellitus (T2DM), characterized by chronic hyperglycemia and insulin resistance, as a risk factor for AD and other cognitive disorders. While studies on insulin action have remained traditionally in the domain of peripheral tissues, the detrimental effects of insulin resistance in the central nervous system on cognitive dysfunction are increasingly being reported in recent clinical and preclinical studies. Brain functions require continuous supply of glucose and oxygen and a tight regulation of metabolic processes. Loss of this metabolic regulation has been proposed to be a contributor to memory dysfunction associated with neurodegeneration. Within the above scenario, this review will focus on the interplay among oxidative stress (OS), insulin resistance and AMPK dysfunctions in the brain by highlighting how these neurotoxic events contribute to neurodegeneration. We provide an overview on the detrimental effects of OS on proteins regulating insulin signaling and how these alterations impact cell metabolic dysfunctions through AMPK dysregulation. Such processes, we assert, are critically involved in the molecular pathways that underlie AD
mTOR in Alzheimer Disease and Its Earlier Stages: Links to Oxidative Damage in the Progression of this Dementing Disorder
No full textAlzheimer’s disease (AD) is the most prevalent form of dementia in the elderly population and has worldwide impact. The etiology of the disease is complex and results from the confluence of multiple mechanisms ultimately leading to neuronal loss and cognitive decline. Among risk factors, aging is the most relevant and accounts for several pathogenic events that contribute to disease-specific toxic mechanisms. Accumulating evidence linked the alterations of the mammalian target of rapamycin (mTOR), a serine/threonine protein kinase playing a key role in the regulation of protein synthesis and degradation, to age-dependent cognitive decline and pathogenesis of AD. To date, growing studies demonstrated that aberrant mTOR signaling in the brain affects several pathways involved in energy metabolism, cell growth, mitochondrial function and proteostasis. Recent advances associated alterations of the mTOR pathway with the increased oxidative stress. Disruption of all these events strongly contribute to age-related cognitive decline including AD. The current review discusses the main regulatory roles of mTOR signaling network in the brain, focusing on its role in autophagy, oxidative stress and energy metabolism. Collectively, experimental data suggest that targeting mTOR in the CNS can be a valuable strategy to prevent/slow the progression of AD
Oxidative stress and mTOR in Down syndrome brain: link to Alzheimer’s dysmetabolism, neuropathology, and possible therapies
No full textThe complexity of Down Syndrome (DS) neurodegeneration involves multiple molecular mechanisms, similar to what observed in Alzheimer’s disease (AD) brain, including the deposition of beta-amyloid (Aβ) into senile plaques and tau hyperphosphorylation in neurofibrillary tangles. Intriguingly, several trisomic genes in addition to being primarily linked to Aβ pathology are responsible for increased oxidative stress (OS) conditions. Indeed, growing studies support the notion that OS contributes to neurodevelopmental defects, neuronal dysfunction, as well as the accelerated aging phenotype of the DS population. Oxidative damage accumulates over the lifespan in parallel with the loss of function of the protein quality control (PQC) systems, including the ubiquitin-proteasome and autophagy. Considering that oxidative damage to proteins induces aggregation, the ability to remove toxic aggregates is essential to prevent neurodegeneration. However, we should consider that the activity of the PQC is compromised by oxidative modification of some of its components thus resulting in increased accumulation of oxidized/misfolded proteins. This scenario highlights that accumulation of oxidative damage together with impairment of protein clearance systems contributes to accelerate neurodegeneration in DS population ultimately resulting in early onset AD neuropathology and dementia
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
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