scholarly journals Oxidative Stress in Alzheimer’s Disease: Why Did Antioxidant Therapy Fail?

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Torbjörn Persson ◽  
Bogdan O. Popescu ◽  
Angel Cedazo-Minguez
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Animal Models ◽  
Clinical Studies ◽  
Current Knowledge ◽  
The Elderly ◽  
Antioxidant Treatment ◽  
Disease Modifying ◽  
Disease Modifying Treatment

Alzheimer’s disease (AD) is the most common form of dementia in the elderly, with increasing prevalence and no disease-modifying treatment available yet. A remarkable amount of data supports the hypothesis that oxidative stress is an early and important pathogenic operator in AD. However, all clinical studies conducted to date did not prove a clear beneficial effect of antioxidant treatment in AD patients. In the current work, we review the current knowledge about oxidative stress in AD pathogeny and we suggest future paths that are worth to be explored in animal models and clinical studies, in order to get a better approach of oxidative imbalance in this inexorable neurodegenerative disease.

Oxidative Stress in the Pathogenesis of Alzheimer’s Disease and Cerebrovascular Disease with Therapeutic Implications

2020 ◽  
Vol 19 (2) ◽  
pp. 94-108 ◽  
Author(s):  
Anamaria Jurcau ◽  
Aurel Simion
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Preventive Measures ◽  
Current Knowledge ◽  
Antioxidant Treatment ◽  
Future Directions ◽  
Therapeutic Implications

The significant gain in life expectancy led to an increase in the incidence and prevalence of dementia. Although vascular risk factors have long and repeatedly been shown to increase the risk of Alzheimer’s Disease (AD), translating these findings into effective preventive measures has failed. In addition, the finding that incident ischemic stroke approximately doubles the risk of a patient to develop AD has been recently reinforced. Current knowledge and pathogenetic hypotheses of AD are discussed. The implication of oxidative stress in the development of AD is reviewed, with special emphasis on its sudden burst in the setting of acute ischemic stroke and the possible link between this increase in oxidative stress and consequent cognitive impairment. Current knowledge and future directions in the prevention and treatment of AD are discussed outlining the hypothesis of a possible beneficial effect of antioxidant treatment in acute ischemic stroke in delaying the onset/progression of dementia.

Molecular Genetics of Early- and Late-Onset Alzheimer’s Disease

2020 ◽  
Vol 20 ◽  
Author(s):  
Md. Sahab Uddin ◽  
Sharifa Hasana ◽  
Md. Farhad Hossain ◽  
Md. Siddiqul Islam ◽  
Tapan Behl ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Massively Parallel Sequencing ◽  
Late Onset ◽  
Current Knowledge ◽  
The Elderly ◽  
Apoe Ε4 ◽  
Sequencing Technologies ◽  
Genetic Components ◽  
Ε4 Allele

: Alzheimer’s disease (AD) is the most common form of dementia in the elderly and this complex disorder is associated with environmental as well as genetic components. Early-onset AD (EOAD) and late-onset AD (LOAD, more common) are major identified types of AD. The genetics of EOAD is extensively understood with three genes variants such as APP, PSEN1, and PSEN2 leading to disease. On the other hand, some common alleles including APOE are effectively associated with LOAD identified but the genetics of LOAD is not clear to date. It has been accounted that about 5% to 10% of EOAD patients can be explained through mutations in the three familiar genes of EOAD. The APOE ε4 allele augmented the severity of EOAD risk in carriers, and APOE ε4 allele was considered as a hallmark of EOAD. A great number of EOAD patients, who are not genetically explained, indicate that it is not possible to identify disease- triggering genes yet. Although several genes have been identified through using the technology of next-generation sequencing in EOAD families including SORL1, TYROBP, and NOTCH3. A number of TYROBP variants were identified through exome sequencing in EOAD patients and these TYROBP variants may increase the pathogenesis of EOAD. The existence of ε4 allele is responsible for increasing the severity of EOAD. However, several ε4 allele carriers live into their 90s that propose the presence of other LOAD genetic as well as environmental risk factors that are not identified yet. It is urgent to find out missing genetics of EOAD and LOAD etiology to discover new potential genetics facets which will assist to understand the pathological mechanism of AD. These investigations should contribute to developing a new therapeutic candidate for alleviating, reversing and preventing AD. This article based on current knowledge represents the overview of the susceptible genes of EOAD, and LOAD. Next, we represent the probable molecular mechanism which might elucidate the genetic etiology of AD and highlight the role of massively parallel sequencing technologies for novel gene discoveries.

scholarly journals Disease‐modifying treatment with I2 imidazoline receptor ligand LSL60101 in an Alzheimer's disease mouse model: A Comparative study with donepezil

2021 ◽  
Author(s):  
Foteini Vasilopoulou ◽  
Sergio Rodríguez‐Arévalo ◽  
Andrea Bagán ◽  
Carmen Escolano ◽  
Christian Griñán‐Ferré ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Comparative Study ◽  
Receptor Ligand ◽  
Imidazoline Receptor ◽  
Disease Modifying ◽  
Disease Modifying Treatment

Metabolomic Alterations in the Blood and Brain in Association with Alzheimer’s Disease: Evidence from in vivo to Clinical Studies

2021 ◽  
pp. 1-28
Author(s):  
Sirawit Sriwichaiin ◽  
Nipon Chattipakorn ◽  
Siriporn C. Chattipakorn
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Studies ◽  
Elderly Population ◽  
The Elderly ◽  
Pathological Findings ◽  
Major Health Problem ◽  
Major Health ◽  
The Brain

Alzheimer’s disease (AD) has become a major health problem among the elderly population. Some evidence suggests that metabolic disturbance possibly plays a role in the pathophysiology of AD. Currently, the study of metabolomics has been used to explore changes in multiple metabolites in several diseases, including AD. Thus, the metabolomics research in AD might provide some information regarding metabolic dysregulations, and their possible associated pathophysiology. This review summarizes the information discovered regarding the metabolites in the brain and the blood from the metabolomics research of AD from both animal and clinical studies. Additionally, the correlation between the changes in metabolites and outcomes, such as pathological findings in the brain and cognitive impairment are discussed. We also deliberate on the findings of cohort studies, demonstrating the alterations in metabolites before changes of cognitive function. All of these findings can be used to inform the potential identity of specific metabolites as possible biomarkers for AD.

scholarly journals Future Therapeutic Perspectives into the Alzheimer’s Disease Targeting the Oxidative Stress Hypothesis

Molecules ◽  
2019 ◽  
Vol 24 (23) ◽  
pp. 4410 ◽  
Author(s):  
Jéssika P. Teixeira ◽  
Alexandre A. de Castro ◽  
Flávia V. Soares ◽  
Elaine F. F. da Cunha ◽  
Teodorico C. Ramalho
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neuronal Cell ◽  
The Elderly ◽  
Oxygen Species ◽  
Chain Reaction ◽  
Radical Chain ◽  
App Metabolism ◽  
Radical Chain Reaction

Alzheimer’s disease (AD) is a neurodegenerative disease that is usually accompanied by aging, increasingly being the most common cause of dementia in the elderly. This disorder is characterized by the accumulation of beta amyloid plaques (Aβ) resulting from impaired amyloid precursor protein (APP) metabolism, together with the formation of neurofibrillary tangles and tau protein hyperphosphorylation. The exacerbated production of reactive oxygen species (ROS) triggers the process called oxidative stress, which increases neuronal cell abnormalities, most often followed by apoptosis, leading to cognitive dysfunction and dementia. In this context, the development of new therapies for the AD treatment is necessary. Antioxidants, for instance, are promising species for prevention and treatment because they are capable of disrupting the radical chain reaction, reducing the production of ROS. These species have also proven to be adjunctive to conventional treatments making them more effective. In this sense, several recently published works have focused their attention on oxidative stress and antioxidant species. Therefore, this review seeks to show the most relevant findings of these studies.

Oxidative Stress Targeting Amyloid Beta Accumulation and Clearance in Alzheimer’s Disease: Insight into Pathological Mechanisms and Therapeutic Strategies

2020 ◽  
Vol 9 (1) ◽  
pp. 22-42
Author(s):  
Sunpreet Kaur ◽  
Puneet Kumar ◽  
Shamsher Singh
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Beta ◽  
Neurodegenerative Disorder ◽  
Acetylcholinesterase Inhibitors ◽  
The Elderly ◽  
Biochemical Alterations ◽  
App Trafficking ◽  
Copper Aluminum

Background: Alzheimer’s disease is the most common neurodegenerative disorder affecting the elderly population and emerges as a leading challenge for the scientific research community. The wide pathological aspects of AD made it a multifactorial disorder and even after long time it’s difficult to treat due to unexplored etiological factors. Methods: The etiogenesis of AD includes mitochondrial failure, gut dysbiosis, biochemical alterations but deposition of amyloid-beta plaques and neurofibrillary tangles are implicated as major hallmarks of neurodegeneration in AD. The aggregates of these proteins disrupt neuronal signaling, enhance oxidative stress and reduce activity of various cellular enzymes which lead to neurodegeneration in the cerebral cortex, neocortex and hippocampus. The metals like copper, aluminum are involved in APP trafficking and promote amyloidbeta aggregation. Similarly, disturbed ubiquitin proteasomal system, autophagy and amyloid- beta clearance mechanisms exert toxic insult in the brain. Result and conclusion : The current review explored the role of oxidative stress in disruption of amyloid homeostasis which further leads to amyloid-beta plaque formation and subsequent neurodegeneration in AD. Presently, management of AD relies on the use of acetylcholinesterase inhibitors, antioxidants and metal chelators but they are not specific measures. Therefore, in this review, we have widely cited the various pathological mechanisms of AD as well as possible therapeutic targets.

scholarly journals Sodium selenate as a disease-modifying treatment for mild–moderate Alzheimer’s disease: an open-label extension study

2021 ◽  
Vol 3 (2) ◽  
pp. e000223
Author(s):  
Lucy Vivash ◽  
Charles B Malpas ◽  
Christopher M Hovens ◽  
Amy Brodtmann ◽  
Steven Collins ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Disease Progression ◽  
Extension Study ◽  
Sodium Selenate ◽  
Cognitive Measures ◽  
Open Label ◽  
Open Label Extension ◽  
Disease Modifying ◽  
Disease Modifying Treatment

IntroductionSodium selenate is a potential disease-modifying treatment for Alzheimer’s disease (AD) which reduces hyperphosphorylated tau through activation of the protein phosphatase 2A enzyme. We have shown sodium selenate to be safe and well tolerated in a 24-week, phase 2a double-blind placebo-controlled randomised controlled trial (RCT), also reporting sodium selenate reduced neurodegeneration on diffusion-weighted MRI. This study assessed the safety and tolerability of chronic sodium selenate treatment (up to 23 months) in patients with AD who had been enrolled in the RCT. Cognitive measures served as secondary outcomes of potential disease-modification.MethodsAn open-label extension study of sodium selenate (10 mg three times a day) in patients with AD who had completed the previous RCT. Twenty-eight patients were enrolled. Patients were regularly monitored for safety, adverse events (AEs) and protocol compliance. Cognitive tests were administered for measures of disease progression.ResultsSixteen patients were discontinued by the sponsor, and 12 discontinued for other reasons. Treatment duration ranged from 6 to 23 months. The majority of AEs were mild (83%), and 33% were treatment-related. Common treatment-related AEs were alopecia (21%) and nail disorder (32%), which both resolved either prior to or following cessation of treatment. Two serious AEs occurred, which were not treatment-related. Alzheimer’s Disease Assessment Scale—Cognitive Subscale 11 score increased 1.8 points over 12 months.DiscussionChronic sodium selenate treatment is safe and well tolerated in patients with AD. Cognitive measures suggest a slowing of disease progression though this could not be confirmed as the study was not controlled. Further research into sodium selenate as a treatment for AD is warranted.

scholarly journals The central role of T-cell memory in Alzheimer’s disease vaccination

2010 ◽  
Vol 1 (1) ◽  
pp. 5
Author(s):  
Brian Giunta ◽  
Amanda Ruscin ◽  
Jon Salemi ◽  
Alan Wolfson ◽  
Francisco Fernandez ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
T Cell ◽  
Animal Models ◽  
The Elderly ◽  
Active Immunization ◽  
T Cell Subsets ◽  
Neurocognitive Deficits ◽  
Cell Reactivity

Alzheimer's disease (AD) is the most common progressive neurodegenerative brain disease as well as the most common dementia among the elderly. In the future as the average lifespan continues to extend, the number of AD patients will continue to grow. Amyloid-beta (Aβ) peptides, in both soluble oligomeric, and insoluble forms, are key in the neuropathogenesis of AD and have thus been a therapeutic target for vaccines. Multiple Aβ vaccination strategies in animal models of AD have demonstrated a marked reduction in both amyloid burden and neurocognitive deficits. Due to the success of these studies, initial human clinical trials of an active Aβ vaccine were conducted. These were discontinued due to the development of meningoencephalitis in approximately 6% of the vaccinated AD patients. Studies examining the brains of Aβ-vaccinated patients developing meningoencephalitis implicate Aβ-reactive T-cell subsets as major components of this deleterious response to active Aβ vaccination. To subvert possible meningoencephalitis resulting from Aβ vaccination second generation of vaccines has been more recently developed. These however have met with little success in humans. To build on these findings, an understanding of the role of T-cells in vaccination against Aβ is presented in this review. Various methods of Aβ immunotherapy are reviewed including studies in both animal models and humans. Recent works suggest that Aβ-derived peptides delivered intranasally or transcutaneously results in effective clearance of Aβ plaques and improvement of cognitive function in animal models of AD. Moreover, undesired T-cell reactivity appeared to be considerably reduced compared with other active immunization strategies. In spite of the past clinical studies, these findings imply that Aβ vaccination may be both efficacious and safe depending route of delivery, adjuvant choice, and Aβ epitope administered.

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