Comparison of Extracellular and Intracellular Blood Compartments Highlights Redox Alterations in Alzheimer's and Mild Cognitive Impairment Patients

Arce-Varas, Noemi; Abate, Giulia; Prandelli, Chiara; Martínez, Carmen Alodia; Cuetos, Fernando; Menéndez, Manuel; Marziano, Mariagrazia; Cabrera-García, David; Fernández-Sánchez, Maria Teresa; Novelli, Antonello; Memo, Maurizio; Uberti, Daniela

doi:10.2174/1567205013666161010125413

Cited by 36 publications

(30 citation statements)

References 43 publications

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“…This aldehyde and protein oxidation markers such as protein carbonyls and 3-nitro tyrosine were significantly elevated in AD lymphocytes and showed a negative correlation with MMSE. Moreover, the superoxide dismutase activity was reduced in AD lymphocytes, showing an impairment in the antioxidant enzymes response [48]. Furthermore, elevated protein levels and activities of NOS2, HO-1, HSP60, HSP72 and thioredoxin reductase were found, which is to be expected when occurring in an oxidizing environment [49].…”

Section: Prospective Ad Biomarkers In Lymphocytesmentioning

confidence: 89%

“…Regulation of cell death seems to be intimately linked to their role as the major intracellular source of ROS, which are mainly generated at Complex I and III of the respiratory chain mitochondrial proteins' oxidative modification causes the mitochondria to increasingly leak superoxide radicals, which may result in an increased production of reactive nitrogen and oxygen species that may consecutively impact cellular functions and death lipid and protein oxidation in mitochondria are considered by several research groups to be potential biomarkers for AD [46,48]. The mitochondrial respiration capacity was determined as oxidative phosphorylation (OXPHOS) and delineated the whole electron transport chain of the four mitochondrial enzymes (complexes I-IV).…”

Section: Prospective Ad Biomarkers In Lymphocytesmentioning

confidence: 99%

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Search for Alzheimer's Disease Biomarkers in Blood Cells: Hypotheses-Driven Approach

et al. 2017

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Current Alzheimer's disease (AD) diagnostics is based on cognitive testing, and detecting amyloid Aβ and τ pathology by brain imaging and assays of cerebrospinal fluid. However, biomarkers identifying complex pathways contributing to pathology are lacking, especially for early AD. Preferably, such biomarkers should be more cost-effective and present in easily available diagnostic tissues, such as blood. Here, we summarize the recent findings of potential early AD molecular diagnostic biomarkers in blood platelets, lymphocytes and erythrocytes. We review molecular alterations which refer to such main hypotheses of AD pathogenesis as amyloid cascade, oxidative and mitochondrial stress, inflammation and alterations in cell cycle regulatory molecules. The major advantage of such biomarkers is the potential ability to indicate individualized therapies in AD patients. Alzheimer's disease (AD) is the most prevalent age-related dementia worldwide and one of the major unmet, increasing medical and economic problems of the modern world. As of 2015, there were an estimated 46.8 million people with dementia worldwide. This number will increase to an estimated 74.7 million in 2030 [1].Among the neuropathological hallmarks of AD are: the progressive loss of brain neurons, synaptic degeneration and the deposition of extracellular amyloid plaques and intracellular neurofibrillary tangles (NFTs) in such regions of the brain as the hippocampus, cortex and amygdala. Amyloid plaques consist mainly of 40-and 42-amino-acid Aβ peptides (Aβ40 and Aβ42). Peptides are proteolytic cleavage products of the Aβ protein precursor (APP) but with no fully elucidated biological function. NFTs are deposits of paired helical filaments composed mainly of hyperphosphorylated τ protein, a microtubule-stabilizing protein that maintains neuronal cell structure and axonal transport. Nevertheless, neither senile plaques nor NFTs are absolute hallmarks of AD dementia, because cognitively intact aged individuals may exhibit both pathological changes upon postmortem brain examination or as assessed by positron emission tomography amyloid and τ imaging agents (amyloid-PET and τ-PET) [2][3][4][5].Clinical AD manifests by aggravating dysfunction and weakening functional cognitive processes, linked to brain neuron loss that is both progressive and permanent [4], and that within several years leads to total dependence on the caregiver and eventually to death. Advances in our knowledge of AD have shown that clinical symptoms usually develop after a long preclinical pathogenic process, lasting for decades, making early AD detection in asymptomatic patients a subject of great interest [4,5]. Increasing proof demonstrates that the therapeutic methods' effectiveness is strictly contingent on the early diagnosis of AD, before the occurrence of massive neuron loss and dementia. This highlights the key importance of biochemical biomarkers for early AD diagnostics. AD diagnostics & demand for novel, improved biomarkersThe broadly accepted recommendations for AD diagnosis...

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Section: Prospective Ad Biomarkers In Lymphocytesmentioning

confidence: 89%

Section: Prospective Ad Biomarkers In Lymphocytesmentioning

confidence: 99%

Search for Alzheimer's Disease Biomarkers in Blood Cells: Hypotheses-Driven Approach

et al. 2017

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“…Furthermore, cell death often leads to amyloid plaque formation in the brain. While mounting evidence implicates ROS in the AD etiology, loosely bound copper ions are very efficient catalysts for ROS generation by a copper-amyloid complex [ 105 , 334 ].…”

Section: Discussionmentioning

confidence: 99%

Copper Toxicity Links to Pathogenesis of Alzheimer’s Disease and Therapeutics Approaches

Ejaz

Wang

Lang

2020

IJMS

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Alzheimer’s disease (AD) is an irreversible, age-related progressive neurological disorder, and the most common type of dementia in aged people. Neuropathological lesions of AD are neurofibrillary tangles (NFTs), and senile plaques comprise the accumulated amyloid-beta (Aβ), loaded with metal ions including Cu, Fe, or Zn. Some reports have identified metal dyshomeostasis as a neurotoxic factor of AD, among which Cu ions seem to be a central cationic metal in the formation of plaque and soluble oligomers, and have an essential role in the AD pathology. Cu-Aβ complex catalyzes the generation of reactive oxygen species (ROS) and results in oxidative damage. Several studies have indicated that oxidative stress plays a crucial role in the pathogenesis of AD. The connection of copper levels in AD is still ambiguous, as some researches indicate a Cu deficiency, while others show its higher content in AD, and therefore there is a need to increase and decrease its levels in animal models, respectively, to study which one is the cause. For more than twenty years, many in vitro studies have been devoted to identifying metals’ roles in Aβ accumulation, oxidative damage, and neurotoxicity. Towards the end, a short review of the modern therapeutic approach in chelation therapy, with the main focus on Cu ions, is discussed. Despite the lack of strong proofs of clinical advantage so far, the conjecture that using a therapeutic metal chelator is an effective strategy for AD remains popular. However, some recent reports of genetic-regulating copper transporters in AD models have shed light on treating this refractory disease. This review aims to succinctly present a better understanding of Cu ions’ current status in several AD features, and some conflicting reports are present herein.

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“…An important feature in AD is the presence of oxidative damages in neuronal lipids and proteins in particular, which clearly links oxidative stress to AD. Oxidative stress can be an early event in the etiology of AD, since markers of oxidation appears in mild cognitive impairment brain regions [210] , [211] . It can have different origins, but the overproduction of ROS is considered as a major contribution.…”

Section: Perspective and Future Researchmentioning

confidence: 99%

Oxidative stress and the amyloid beta peptide in Alzheimer’s disease

et al. 2018

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Oxidative stress is known to play an important role in the pathogenesis of a number of diseases. In particular, it is linked to the etiology of Alzheimer’s disease (AD), an age-related neurodegenerative disease and the most common cause of dementia in the elderly. Histopathological hallmarks of AD are intracellular neurofibrillary tangles and extracellular formation of senile plaques composed of the amyloid-beta peptide (Aβ) in aggregated form along with metal-ions such as copper, iron or zinc. Redox active metal ions, as for example copper, can catalyze the production of Reactive Oxygen Species (ROS) when bound to the amyloid-β (Aβ). The ROS thus produced, in particular the hydroxyl radical which is the most reactive one, may contribute to oxidative damage on both the Aβ peptide itself and on surrounding molecule (proteins, lipids, …). This review highlights the existing link between oxidative stress and AD, and the consequences towards the Aβ peptide and surrounding molecules in terms of oxidative damage. In addition, the implication of metal ions in AD, their interaction with the Aβ peptide and redox properties leading to ROS production are discussed, along with both in vitro and in vivo oxidation of the Aβ peptide, at the molecular level.

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Comparison of Extracellular and Intracellular Blood Compartments Highlights Redox Alterations in Alzheimer's and Mild Cognitive Impairment Patients

Cited by 36 publications

References 43 publications

Search for Alzheimer's Disease Biomarkers in Blood Cells: Hypotheses-Driven Approach

Search for Alzheimer's Disease Biomarkers in Blood Cells: Hypotheses-Driven Approach

Copper Toxicity Links to Pathogenesis of Alzheimer’s Disease and Therapeutics Approaches

Oxidative stress and the amyloid beta peptide in Alzheimer’s disease

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