1,721,019 research outputs found
Copper imbalance in Alzheimer’s disease: Overview of the exchangeable copper component in plasma and the intriguing role albumin plays
No full textEssential metals are vital elements for human biology. Iron, copper, and zinc are all essential for life. Trace metal dyshomeostasis has been linked to cognitive deterioration and in particular to a disturbance in the regulation of copper (Cu), characterized by an increase in serum Cu not bound to ceruloplasmin (nCp-Cu also known as "free" copper). It is thought to play a role in the development of Alzheimer's disease (AD), the most common form of dementia. Copper homeostasis is finely regulated in our bodies and the expansion of exchangeable nCp-Cu is symptom of the breakdown of this homeostasis, which affects myriad biological pathways. If not structurally bound to enzymes or coordinated by proteins, copper generates free radicals via Haber-Weiss and Fenton reactions. Human Serum Albumin (HSA) is the most abundant serum protein and the main protein exchanging copper in the nCp-Cu pool. Copper coordinated by HSA is in equilibrium with copper coordinated by other small copper chelators circulating in the blood stream in a dynamic and exchangeable manner dependent on environmental osmolarity, oxidation state, pH and compounds' functions. Albumin is susceptible to glycation starting from Maillard reaction, carbohydrates, in particular glucose, form advanced glycation end-products (AGEs). AGE-albumin is one of this products. Free radicals and free metals in circulation accelerate this cross-linking of protein with carbohydrates. Modified albumins are also significantly less effective than native forms in avoiding the aggregation of A beta, the main component of the amyloid plaques in the AD brain. The current review aims to provide insight into the coordination chemistry of copper in plasma with a special glance toward the exchangeable copper coordinated by albumin, to explore how aberrant regulations of this interaction are linked to the aetiology of AD. (C) 2018 Elsevier B.V. All rights reserved
Copper and Zinc Dysregulation in Alzheimer's Disease
No full textAlzheimer's disease (AD) is one of the most common forms of dementia. Despite a wealth of knowledge on the molecular mechanisms involved in AD, current treatments have mainly focused on targeting amyloid beta (A beta) production, but have failed to show significant effects and efficacy. Therefore, a critical reconsideration of the multifactorial nature of the disease is needed. AD is a complex multifactorial disorder in which, along with A beta and tau, the convergence of polygenic, epigenetic, environmental, vascular, and metabolic factors increases the global susceptibility to the disease and shapes its course. One of the cofactors converging on AD is the dysregulation of brain metals. In this review, we focus on the role of AD-related neurodegeneration and cognitive decline triggered by the imbalance of two endogenous metals: copper and zinc
Non-ceruloplasmin bound copper and ATP7B gene variants in Alzheimer's disease
No full textATP7B, a protein mainly expressed in the hepatocytes, is a copper chaperone that loads the metal into the serum copper-protein ceruloplasmin during its synthesis and also escorts superfluous copper into the bile, by a sophisticated trafficking mechanism. Impaired function of this ATPase is associated with a well-known inborn error of copper metabolism, Wilson's disease (WD). Several mutations of ATP7B are known, involving different regions of the protein, thus resulting in a plethora of phenotypes in WD patients. It is a consolidated notion that copper dysmetabolism occurs in Alzheimer's disease (AD) as well. Besides the molecular mechanisms relating copper to the protein hallmarks of this disease and neurodegeneration, more recently the observation that a free-copper in the serum, not bound to ceruloplasmin (non-Cp-Cu), characterizes AD patients, prompted our research to identify possible genetic defects of the ATP7B gene in AD patients. Four specific single nucleotide polymorphisms and a WD rare mutation have a statistical association with AD. They contribute to characterize a copper subtype of AD. Additional facets of this AD phenotype, typified by higher levels of non-Cp-Cu, are presented and discussed in the framework of copper failure as an accelerator risk factor of neurological disorders with different aetiology
Towards a Unified Vision of Copper Involvement in Alzheimer's Disease: A Review Connecting Basic, Experimental, and Clinical Research
No full textAutomation of o-dianisidine assay for ceruloplasmin activity analyses: usefulness of investigation in Wilson's disease and in hepatic encephalopathy
No full textRole of Copper in the Onset of Alzheimer's Disease Compared to Other Metals
No full textAlzheimer's disease (AD) is a neurodegenerative disorder that is characterized by amyloid plaques in patients' brain tissue. The plaques are mainly made of beta-amyloid peptides and trace elements including Zn2+, Cu2+, and Fe2+. Some studies have shown that AD can be considered a type of metal dyshomeostasis. Among metal ions involved in plaques, numerous studies have focused on copper ions, which seem to be one of the main cationic elements in plaque formation. The involvement of copper in AD is controversial, as some studies show a copper deficiency in AD, and consequently a need to enhance copper levels, while other data point to copper overload and therefore a need to reduce copper levels. In this paper, the role of copper ions in AD and some contradictory reports are reviewed and discussed
In silico investigation of the ATP7B gene: insights from functional prediction of non-synonymous substitution to protein structure
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