Copper and Zinc Dysregulation in Alzheimer’s Disease

Sensi, Stefano L.; Granzotto, Alberto; Siotto, Mariacristina; Squitti, Rosanna

doi:10.1016/j.tips.2018.10.001

Cited by 212 publications

(164 citation statements)

References 106 publications

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“…One study proposes a mechanism where rhodopsin misfolding ultimately contributes to retinal degeneration and the visual changes that are seen in both retinitis pigmentosa and Alzheimer's disease (Stojanovic et al, 2004). Surprisingly, recent research has suggested that the dysregulation of brain metals, such as copper and zinc, occurs in AD (Sensi et al, 2018). In addition, zinc supplementation positively affects neurotrophic signaling and activation of the brain-derived neurotrophic factor (BDNF)-TrkB axis (Hwang et al, 2005;Sensi et al, 2009;Corona et al, 2010).…”

Section: Rhodopsin and Alzheimer's Diseasementioning

confidence: 99%

Rhodopsin: A Potential Biomarker for Neurodegenerative Diseases

Lenahan

Sanghavi²,

Huang

et al. 2020

Front. Neurosci.

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Retinal alterations have recently been associated with numerous neurodegenerative diseases. Rhodopsin is a G-protein coupled receptor found in the rod cells of the retina. As a biomarker associated with retinal thinning and degeneration, it bears potential in the early detection and monitoring of several neurodegenerative diseases. In this review article, we summarize the findings of correlations between rhodopsin and several neurodegenerative disorders as well as the potential of a novel technique, cSLO, in the quantification of rhodopsin.

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Section: Rhodopsin and Alzheimer's Diseasementioning

confidence: 99%

Rhodopsin: A Potential Biomarker for Neurodegenerative Diseases

Lenahan

Sanghavi²,

Huang

et al. 2020

Front. Neurosci.

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“…Similarly, multiple peptides representing the copper and iron-handling protein ceruloplasmin were found to vary signi cantly between groups at q < 0.05. Copper storage and regulation abnormalities have been implicated in the pathogenesis of Alzheimer's disease (reviewed) [57] and HIV-associated neurocognitive disorder [58], and alterations in ceruloplasmin activity have been associated with increased Alzheimer's disease risk [59,60]. Finally, the axonal secretory sorting receptor secretogranin-III, represented by a single peptide with q < 0.05, has been implicated in the mechanisms driving amyloid-mediated neurodegeneration in Alzheimer's disease [61].…”

Section: Discussionmentioning

confidence: 99%

Cerebrospinal Fluid Proteomic Changes in Older Non-Cardiac Surgical Patients with Postoperative Cognitive Dysfunction

VanDusen

et al. 2020

Preprint

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Background: Postoperative cognitive dysfunction (POCD) is a syndrome of cognitive deficits that occurs in 10-40% of patients age > 60 within 1-12 months after surgery, hypothesized to be caused in part by neuroinflammation. However, the specific neuroinflammatory pathways involved remain unclear. Unbiased mass spectrometry-based proteomic analyses have been used to identify neuro-inflammatory pathways in multiple neurologic diseases and syndromes but have not yet been used in the POCD field. Thus, we used unbiased mass spectrometry-based proteomics to compare cerebrospinal fluid (CSF) samples from patients with and without POCD to identify potential neuroinflammatory pathways for further investigation in future studies. Methods: We performed unbiased LC-MS/MS proteomics on immunodepleted CSF samples obtained before, 24 hours, and 6 weeks after major non-cardiac surgery in older adults who developed (n=8) or did not develop POCD (n=6). General linear mixed models were used to identify peptides and proteins with intensity differences between groups or over time by groups. Kyoto Encyclopedia of Genes and Genomes analysis was used to identify pathways containing proteins/peptides with q values < 0.25 in the mixed model. Results: Mass spectrometry quantified 8258 peptides from 1222 proteins in >50% of patient samples at all three time points. Twelve peptides from 11 proteins showed differences in expression over time between groups (POCD vs non-POCD) at q < 0.05, including several from proteins previously implicated in neurodegenerative disease pathophysiology. Additionally, 283 peptides from 182 proteins were identified with trend-level differences (q < 0.25) in expression over time between these patient groups. Of these 283 peptides with trend-level significance, pathway analysis revealed that 50 of them were from 17 proteins that mapped to the complement and coagulation pathways (q=2.44*10-13).Conclusions: These data demonstrate the feasibility of performing unbiased mass spectrometry on perioperative CSF samples to identify peptides, proteins, and pathways associated with POCD. Additionally, they provide hypothesis-generating evidence for CSF complement and coagulation pathway changes in patients with POCD.

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“…From a molecular point of view, AD is characterized by extracellular deposits of β-amyloid protein accumulated in the brain, ultimately leading to neuronal loss [50]. Condensation of β-amyloid in plaques is linked to high concentrations of Cu(II) and Zn(II) in the neocortical tissue, therefore suggesting a role of metal imbalance in the onset of AD [51][52][53]. Moreover, β-amyloid binds and reduces Cu(II) to Cu(I), inducing electron transfer to molecular oxygen with the formation of H 2 O 2 , leading to apoptotic cell death [51].…”

Section: Alzheimer's Diseasementioning

confidence: 99%

Current Biomedical Use of Copper Chelation Therapy

Baldari

Rocco

Toietta

2020

IJMS

115

105

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Copper is an essential microelement that plays an important role in a wide variety of biological processes. Copper concentration has to be finely regulated, as any imbalance in its homeostasis can induce abnormalities. In particular, excess copper plays an important role in the etiopathogenesis of the genetic disease Wilson’s syndrome, in neurological and neurodegenerative pathologies such as Alzheimer’s and Parkinson’s diseases, in idiopathic pulmonary fibrosis, in diabetes, and in several forms of cancer. Copper chelating agents are among the most promising tools to keep copper concentration at physiological levels. In this review, we focus on the most relevant compounds experimentally and clinically evaluated for their ability to counteract copper homeostasis deregulation. In particular, we provide a general overview of the main disorders characterized by a pathological increase in copper levels, summarizing the principal copper chelating therapies adopted in clinical trials.

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Copper and Zinc Dysregulation in Alzheimer’s Disease

Cited by 212 publications

References 106 publications

Rhodopsin: A Potential Biomarker for Neurodegenerative Diseases

Rhodopsin: A Potential Biomarker for Neurodegenerative Diseases

Cerebrospinal Fluid Proteomic Changes in Older Non-Cardiac Surgical Patients with Postoperative Cognitive Dysfunction

Current Biomedical Use of Copper Chelation Therapy

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