Potential oxidative stress biomarkers of mild cognitive impairment due to Alzheimer disease

García‐Blanco, Ana; Baquero, Miguel; Vento, Máximo; Gil, Esperanza; Bataller, Luís; Cháfer-Pericás, Consuelo

doi:10.1016/j.jns.2017.01.020

Cited by 87 publications

(58 citation statements)

References 69 publications

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“…When this balance is disturbed, the body responds to oxidative stress by producing free radicals, including Neurons in the brain are extremely sensitive to free radicals. DNA damage, protein oxidation, lipid peroxidation, and production of advanced glycosylation end products (AGEs) in the AD brains are usually related to free radical attacks and metal imbalances [76,77]. Oxidative stress has been wildly detected in AD patients and the animal models, and the imbalance of metal ions, such as iron, copper, zinc, and calcium, can cause oxidative stress, tau hyperphosphorylation, Aβ deposition, cross-linking of nerve fibers and nerve cell damages, which are closely related to the pathogenesis of AD.…”

Section: Role Of Metal Ions In Oxidative Stressmentioning

confidence: 99%

Current understanding of metal ions in the pathogenesis of Alzheimer’s disease

Wang

Yin

Liu

et al. 2020

Transl Neurodegener

251

188

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Background: The homeostasis of metal ions, such as iron, copper, zinc and calcium, in the brain is crucial for maintaining normal physiological functions. Studies have shown that imbalance of these metal ions in the brain is closely related to the onset and progression of Alzheimer's disease (AD), the most common neurodegenerative disorder in the elderly. Main body: Erroneous deposition/distribution of the metal ions in different brain regions induces oxidative stress. The metal ions imbalance and oxidative stress together or independently promote amyloid-β (Aβ) overproduction by activating βor γ-secretases and inhibiting α-secretase, it also causes tau hyperphosphorylation by activating protein kinases, such as glycogen synthase kinase-3β (GSK-3β), cyclin-dependent protein kinase-5 (CDK5), mitogenactivated protein kinases (MAPKs), etc., and inhibiting protein phosphatase 2A (PP2A). The metal ions imbalances can also directly or indirectly disrupt organelles, causing endoplasmic reticulum (ER) stress; mitochondrial and autophagic dysfunctions, which can cause or aggravate Aβ and tau aggregation/accumulation, and impair synaptic functions. Even worse, the metal ions imbalance-induced alterations can reversely exacerbate metal ions misdistribution and deposition. The vicious cycles between metal ions imbalances and Aβ/tau abnormalities will eventually lead to a chronic neurodegeneration and cognitive deficits, such as seen in AD patients. Conclusion: The metal ions imbalance induces Aβ and tau pathologies by directly or indirectly affecting multiple cellular/ subcellular pathways, and the disrupted homeostasis can reversely aggravate the abnormalities of metal ions transportation/ deposition. Therefore, adjusting metal balance by supplementing or chelating the metal ions may be potential in ameliorating AD pathologies, which provides new research directions for AD treatment.

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Section: Role Of Metal Ions In Oxidative Stressmentioning

confidence: 99%

Current understanding of metal ions in the pathogenesis of Alzheimer’s disease

Wang

Yin

Liu

et al. 2020

Transl Neurodegener

251

188

View full text Add to dashboard Cite

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“…Altered proteins produce molecules that damage DNA and RNA. All these oxidative stress products accumulate and trigger AD development [54].…”

Section: Oxidative Stress Biomarkersmentioning

confidence: 99%

Reasons for Failed Trials of Disease-Modifying Treatments for Alzheimer Disease and Their Contribution in Recent Research

et al. 2019

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Despite all scientific efforts and many protracted and expensive clinical trials, no new drug has been approved by FDA for treatment of Alzheimer disease (AD) since 2003. Indeed, more than 200 investigational programs have failed or have been abandoned in the last decade. The most probable explanations for failures of disease-modifying treatments (DMTs) for AD may include late initiation of treatments during the course of AD development, inappropriate drug dosages, erroneous selection of treatment targets, and mainly an inadequate understanding of the complex pathophysiology of AD, which may necessitate combination treatments rather than monotherapy. Clinical trials’ methodological issues have also been criticized. Drug-development research for AD is aimed to overcome these drawbacks. Preclinical and prodromal AD populations, as well as traditionally investigated populations representing all the clinical stages of AD, are included in recent trials. Systematic use of biomarkers in staging preclinical and prodromal AD and of a single primary outcome in trials of prodromal AD are regularly integrated. The application of amyloid, tau, and neurodegeneration biomarkers, including new biomarkers—such as Tau positron emission tomography, neurofilament light chain (blood and Cerebrospinal fluid (CSF) biomarker of axonal degeneration) and neurogranin (CSF biomarker of synaptic functioning)—to clinical trials allows more precise staging of AD. Additionally, use of Bayesian statistics, modifiable clinical trial designs, and clinical trial simulators enrich the trial methodology. Besides, combination therapy regimens are assessed in clinical trials. The above-mentioned diagnostic and statistical advances, which have been recently integrated in clinical trials, are relevant to the recent failures of studies of disease-modifying treatments. Their experiential rather than theoretical origins may better equip potentially successful drug-development strategies.

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“…The "late-onset" accumulation of amyloid-beta also raises the question of how "age" is translated in terms of cellular/tissue environment, leading to the increase in amyloid-beta accumulation. Existing interrelating theories and interpretations include (i) increased inflammation [75][76][77], (ii) increased oxidative stress [78][79][80], (iii) mitochondrial dysfunction [81], (iv) calcium homeostasis defect [82], (v) accumulation of mutations [83], (vi) stem cell fatigue and depletion [84], (vii) decreased proper brain-immune crosstalk [85], (viii) brain blood barrier dysfunction [86], (ix) decreased amyloid-beta clearance [87], (x) increased amyloid-beta deposition [88], and (xi) synaptic senescence [89,90]. In his book The end of Alzheimer's (2017) [91], Dale Bredesen listed 36 facilitators, which can be roughly categorized as inflammation, lack of nutrition and/or hormone, and toxins.…”

Section: Late-onset Accumulation Of Amyloid-beta In Sgo1 Brainmentioning

confidence: 99%

Critical role of mitosis in spontaneous late-onset Alzheimer’s disease; from a Shugoshin 1 cohesinopathy mouse model

et al. 2018

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From early-onset Alzheimer's disease (EOAD) studies, the amyloid-beta hypothesis emerged as the foremost theory of the pathological causes of AD. However, how amyloid-beta accumulation is triggered and progresses toward senile plaques in spontaneous late-onset Alzheimer's disease (LOAD) in humans remains unanswered. Various LOAD facilitators have been proposed, and LOAD is currently considered a complex disease with multiple causes. Mice do not normally develop LOAD. Possibly due to the multiple causes, proposed LOAD facilitators have not been able to replicate spontaneous LOAD in mice, representing a disease modeling issue. Recently, we reported spontaneous late-onset development of amyloid-beta accumulation in brains of Shugoshin 1 (Sgo1) haploinsufficient mice, a cohesinopathy-mediated chromosome instability model. The result for the first time expands disease relevance of mitosis studies to a major disease other than cancers. Reverse-engineering of the model would shed light on the process of late-onset amyloid-beta accumulation in the brain and spontaneous LOAD development, and contribute to development of interventions for LOAD. This review will discuss the Sgo1 model, our current "three-hit hypothesis" regarding LOAD development with an emphasis on critical role of prolonged mitosis in amyloid-beta accumulation, and implications for human LOAD intervention and treatment. Abbreviations: Alzheimer's disease (AD); Late-onset Alzheimer's disease (LOAD); Early-onset Alzheimer's disease (EOAD); Shugoshin-1 (Sgo1); Chromosome Instability (CIN); apolipoprotein (Apoe); Central nervous system (CNS); Amyloid precursor protein (APP); N-methyl-d-aspartate (NMDA); Hazard ratio (HR); Cyclin-dependent kinase (CDK); Chronic Atrial Intestinal Dysrhythmia (CAID); beta-secretase 1 (BACE); phosphor-Histone H3 (p-H3); Research and development (R&D); Non-steroidal anti-inflammatory drugs (NSAIDs); Brain blood barrier (BBB).

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Potential oxidative stress biomarkers of mild cognitive impairment due to Alzheimer disease

Cited by 87 publications

References 69 publications

Current understanding of metal ions in the pathogenesis of Alzheimer’s disease

Current understanding of metal ions in the pathogenesis of Alzheimer’s disease

Reasons for Failed Trials of Disease-Modifying Treatments for Alzheimer Disease and Their Contribution in Recent Research

Critical role of mitosis in spontaneous late-onset Alzheimer’s disease; from a Shugoshin 1 cohesinopathy mouse model

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