Aluminium, iron, zinc and copper influence the in vitro formation of amyloid fibrils of Aβ42 in a manner which may have consequences for metal chelation therapy in Alzheimer's disease

House, Emily; Collingwood, Joanna F.; Khan, Ayesha; Korchazkina, Olga; Berthon, Guy; Exley, Christopher

doi:10.3233/jad-2004-6310

Cited by 282 publications

(223 citation statements)

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“…Then, as a function of parameters like solvent's pH and metal concentration, these two ions have shown different behaviors; in particular, under physiological conditions, the amyloid peptide has a higher propensity to bind zinc, whereas, under mildly acidic conditions, as in physiological acidosis following an inflammatory process, copper is preferentially bound; in other words, zinc can protect against copper toxicity, which is induced by acidosis [12,13]. In addition, studies with different concentrations of copper and zinc have shown that these metals prevent fibril formation of amyloid peptide by promoting the formation of no fibril aggregates [8,[14][15][16], like oligomeric aggregates that are more neurotoxic than the same fibrils [17][18][19][20][21][22][23][24]. Finally, other results obtained by structural studies, have shown that this peptide has two metal binding sites with higher and lower affinity: copper in high affinity site is coordinated in a planar configuration with three histidines and terminus or Tyr10 and this binding site is able to bind also a zinc ion [21,22,25].…”

Section: Introductionmentioning

confidence: 99%

Thermal aggregation of β-lactoglobulin in presence of metal ions

Navarra

Leone

Militello

2007

Biophysical Chemistry

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT AbstractIn this work, we report a study on the effects of zinc and copper ions on the heat-induced aggregation of β−Lactoglobulin (BLG). Kinetics investigations on aggregates growth by light scattering measurements and on secondary structure changes by FT-IR absorption measurementsshow the different role played by two metals during the whole process. In particular, the presence of zinc in solution promotes the formation of aggregates of BLG at a lower temperature than the copper. Then, fixed the temperature, formation of a large amount of aggregates, with a large dimension, is observed for the Zn-BLG in shorter time; on the contrary, the presence of the copper in solution does not affect the aggregation process but the secondary structure changes and the formation of different stronger intermolecular H-bonds, which probably lead to build a network of bonds that takes towards gelation. Our studies show as time evolution of aggregation process of BLG is dramatically affected by the presence of metal ions in solution and structural protein modifications are induced by different divalent metal ions.

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Section: Introductionmentioning

confidence: 99%

Thermal aggregation of β-lactoglobulin in presence of metal ions

Navarra

Leone

Militello

2007

Biophysical Chemistry

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“…Transition metal ion chelators-One hypothesis that remains viable is that transition metal ions, including Al (III), Fe (III), Zn (II), and Cu (II), cause neurotoxicity and neurodegeneration (241)(242)(243), including in the earliest stages of AD (244). Excess accumulation of transition metal ions promotes oxidative stress, apoptosis, and aggregation and fibrillarization of hyper-phosphorylated tau (245) and AβPP-Aβ42 (243,246). Oxidative stress is mediated by the formation of hydroxyl radicals following interactions between iron and hydrogen peroxide.…”

Section: Radical Scavengers-epidemiological Studies Suggested That Lomentioning

confidence: 99%

Therapeutic targets of brain insulin resistance in sporadic Alzheimer s disease

Monte

2012

Front Biosci

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Growing evidence supports roles for brain insulin and insulin-like growth factor (IGF) resistance and metabolic dysfunction in the pathogenesis of Alzheimer's disease (AD). Whether the underlying problem stems from a primary disorder of central nervous system (CNS) neurons and glia, or secondary effects of systemic diseases such as obesity, Type 2 diabetes, or metabolic syndrome, the end-results include impaired glucose utilization, mitochondrial dysfunction, increased oxidative stress, neuroinflammation, and the propagation of cascades that result in the accumulation of neurotoxic misfolded, aggregated, and ubiquitinated fibrillar proteins. This article reviews the roles of impaired insulin and IGF signaling to AD-associated neuronal loss, synaptic disconnection, tau hyperphosphorylation, amyloid-beta accumulation, and impaired energy metabolism, and discusses therapeutic strategies and lifestyle approaches that could be used to prevent, delay the onset, or reduce the severity of AD. Finally, it is critical to recognize that AD is heterogeneous and has a clinical course that fully develops over a period of several decades. Therefore, early and multi-modal preventive and treatment approaches should be regarded as essential. KeywordsAmyloid; Anti-oxidants; Brain diabetes; Brain insulin resistance; Incretins; Insulin; Insulin sensitizers; Liver-Brain-Axis; Metal Chelation; Neuroprotection; Nitrosamine; Oxidative Stress; Polyphenols; Statins; Streptozotocin; Tau; Type 3 diabetes INTRODUCTIONThe gold standard for definitively diagnosing AD is to perform a postmortem examination of the brain, with the objective of demonstrating beyond-normal aging associated densities of neurofibrillary tangles, neuritic plaques, and amyloid-beta 40-42 kD fragments of amyloid beta precursor protein (AβPP-Aβ) deposits in corticolimbic structures, bearing in mind that neurodegeneration frequently involves multiple other cortical regions as well. The common thread among these characteristic lesions is that they harbor insoluble aggregates of abnormally phosphorylated and ubiquitinated tau, and neurotoxic AβPP-Aβ in the form of Send correspondence to: Suzanne M. de la Monte, Rhode Island Hospital, 55 Claverick Street, Room 419, Providence, RI. 02903, Tel: 401-444-7364, Fax: 401-444-2939, Suzanne_DeLaMonte_MD@Brown.edu. HHS Public Access Author manuscriptFront Biosci (Elite Ed). Author manuscript; available in PMC 2015 August 26. Published in final edited form as:Front Biosci (Elite Ed). ; 4: 1582-1605. Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript oligomers, fibrillar aggregates, or extracellular plaques. Secreted AβPP-Aβ oligomers have been demonstrated to be neurotoxic and to inhibit hippocampal long-term potentiation, i.e. synaptic plasticity (1).To improve diagnosis and treatment, we must learn to connect the development and progression of neurodegeneration with molecular, biochemical, physiological, neuroimaging, and clinical abnormalities in AD. Several strategies could be taken to advance this proc...

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“…67 Indeed, the prototype iron chelator, deferrioxamine (DFO), prevented the formation of ␤-pleated sheets of A␤ and dissolved preformed ␤-pleated sheets of plaque-like amyloid. 68 Also, ironinduced aggregation of hyperphosphorylated (tau), the major constituent of neurofibrillary tangles. 69 A direct link between iron metabolism and AD pathogenesis was provided recently by Rogers et al 70 who described the presence of an IRE in the 5' untranslated region (5'UTR) of the APP transcript.…”

Section: Selected Strategies In the Development Of Multifunctional Drmentioning

confidence: 99%

Multifunctional Neuroprotective Derivatives of Rasagiline as Anti-Alzheimer's Disease Drugs

et al. 2009

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Summary:The recent therapeutic approach in which drug candidates are designed to possess diverse pharmacological properties and act on multiple targets has stimulated the development of the multimodal drugs, ladostigil (TV3326) [(Npropargyl-(3R) aminoindan-5yl)-ethyl methyl carbamate] and the newly designed multifunctional antioxidant iron chelator, M-30 (5-[N-methyl-N-propargylaminomethyl]-8-hydroxyquinoline). Ladostigil combines, in a single molecule, the neuroprotective/neurorestorative effects of the novel anti-Parkinsonian drug and selective monoamine oxidase (MAO)-B inhibitor, rasagiline (Azilect, Teva Pharmaceutical Co.) with the cholinesterase (ChE) inhibitory activity of rivastigmine. A second derivative of rasagiline, M-30 was developed by amalgamating the propargyl moiety of rasagiline into the skeleton of our novel brain permeable neuroprotective iron chelator, VK-28. Preclinical experiments showed that both compounds have anti-Alzheimer's disease activities and thus, the clinical development is oriented toward treatment of this type of dementia. This review discusses the multimodal effects of two rasagilinecontaining hybrid molecules, namely ladostigil and M-30, concerning their neuroprotective molecular mechanisms in vivo and in vitro, including regulation of amyloid precursor protein processing, activation of protein kinase C, and mitogen-activated protein kinase signaling pathways, inhibition of cell death markers and upregulation of neurotrophic factors. Altogether, these scientific findings make these multifunctional compounds potentially valuable drugs for the treatment of Alzheimer's disease.

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Aluminium, iron, zinc and copper influence the in vitro formation of amyloid fibrils of Aβ42 in a manner which may have consequences for metal chelation therapy in Alzheimer's disease

Cited by 282 publications

References 0 publications

Thermal aggregation of β-lactoglobulin in presence of metal ions

Thermal aggregation of β-lactoglobulin in presence of metal ions

Therapeutic targets of brain insulin resistance in sporadic Alzheimer s disease

Multifunctional Neuroprotective Derivatives of Rasagiline as Anti-Alzheimer's Disease Drugs

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