The modulation of metal bio‐availability as a therapeutic strategy for the treatment of Alzheimer's disease

Crouch, Peter J.; White, Anthony R.; Bush, Ashley I.

doi:10.1111/j.1742-4658.2007.05918.x

Cited by 70 publications

(55 citation statements)

References 86 publications

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“…It is known that Cu 2ϩ levels in the brain increase with age (2); thus, our observations should refocus attention on loss of Cu 2ϩ homeostasis as a possible risk factor in AD. Cu 2ϩ chelators are being investigated in clinical trials as a potential therapy for AD (2,65,66).…”

Section: Discussionmentioning

confidence: 99%

Substoichiometric Levels of Cu2+ Ions Accelerate the Kinetics of Fiber Formation and Promote Cell Toxicity of Amyloid-β from Alzheimer Disease

Sarell

Wilkinson

Viles

2010

Journal of Biological Chemistry

181

218

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A role for Cu 2؉ ions in Alzheimer disease is often disputed, as it is believed that Cu 2؉ ions only promote nontoxic amorphous aggregates of amyloid-␤ (A␤). In contrast with currently held opinion, we show that the presence of substoichiometric levels of Cu 2؉ ions in fact doubles the rate of production of amyloid fibers, accelerating both the nucleation and elongation of fiber formation. We suggest that binding of Cu 2؉ ions at a physiological pH causes A␤ to approach its isoelectric point, thus inducing self-association and fiber formation. We further show that Cu 2؉ ions bound to A␤ are consistently more toxic to neuronal cells than A␤ in the absence of Cu 2؉ ions, whereas Cu 2؉ ions in the absence of A␤ are not cytotoxic. The degree of Cu-A␤ cytotoxicity correlates with the levels of Cu 2؉ ions that accelerate fiber formation. We note the effect appears to be specific for Cu 2؉ ions as Zn 2؉ ions inhibit the formation of fibers. An active role for Cu 2؉ ions in accelerating fiber formation and promoting cell death suggests impaired copper homeostasis may be a risk factor in Alzheimer disease. Alzheimer disease (AD)2 is characterized by extracellular amyloid plaques, composed predominantly of fibrillar amyloid-␤ peptide (A␤), a 39 -43-residue peptide. Genetic alterations underlying familial AD are associated with mutations or increased production of A␤, indicating that A␤ plays a central role in the disease (1).A notable characteristic of AD is altered metal ion concentrations in the brain and disrupted metal ion homeostasis (2). Cu 2ϩ ions are found concentrated within senile plaques of AD patients directly bound to A␤ (3-5). Recent in vivo studies using a Drosophila model of AD have shown that impaired copper homeostasis enhances the toxic effects of A␤ (6). Furthermore, copper in a cholesterol high diet induces amyloid plaques and learning deficits in a rabbit model of AD (7). Other in vivo studies have shown that copper homeostasis can influence AD pathology. In contrast to the Drosophila model, transgenic mice have shown a reduced AD pathology with increased intracellular copper levels (8 -10).Although studies of A␤ neurotoxicity suggest that small diffusible oligomers, rather than mature amyloid fibers, are the more toxic form (11, 12), there remains strong evidence suggesting that amyloid plaques, or possibly intermediates of the fibrils, are critical in neuronal toxicity (13,14). A␤ oligomers may be precursors of fiber formation and may also arise from fiber fragmentation. Alternatively, oligomers may be in competition with fiber formation. Both possibilities require the self-association of monomeric A␤, and thus factors that affect fibrillization will also influence oligomer generation.The mechanism by which A␤ is toxic is hotly debated (11, 15). It has been proposed that A␤ can form ion channels or pores or can thin the membrane, all of which will cause membrane leakage and loss of cellular Ca 2ϩ ion homeostasis. One popular hypothesis is that the membrane integrity is compromised by lipid peroxida...

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Section: Discussionmentioning

confidence: 99%

Substoichiometric Levels of Cu2+ Ions Accelerate the Kinetics of Fiber Formation and Promote Cell Toxicity of Amyloid-β from Alzheimer Disease

Sarell

Wilkinson

Viles

2010

Journal of Biological Chemistry

181

218

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“…Dentre os elementos determinados no encéfalo humano, a participação dos metais na DA têm recebido grande destaque (Finefrock et al, 2003;Donnelly et al, 2007;Crouch et al, 2007;Bush, 2003;Bush e Curtain, 2008;Bush, 2000;Bush, 2002). Segundo Crouch et al (2007) a perda da homeostase dos biometais é uma característica consistente no encéfalo de portadores de DA.…”

Section: Elementos Traço E Neurociênciasunclassified

“…Segundo Crouch et al (2007) a perda da homeostase dos biometais é uma característica consistente no encéfalo de portadores de DA.…”

Section: Elementos Traço E Neurociênciasunclassified

“…O Fe é um co-fator universal para geração de energia na mitocôndria e suporta o crescimento e diferenciação de todos os tipos celulares (Roskams e Connor, 1994;Crouch et al, 2007). No sistema nervoso central, o Fe é um componente chave dos sistemas responsáveis pela mielinização e a síntese de vários neurotransmissores (Roskams e Connor, 1994;Donnelly et al, 2007), havendo suporte na literatura para estabelecer conceitos de que um suprimento de Fe é essencial para o desenvolvimento neurológico normal (Roskams e Connor, 1994).…”

Section: Ferro Na Doença De Alzheimerunclassified

“…Existem mais de 200 enzimas identificadas contendo este elemento (Panayi et al, 2002). Talvez o mais crítico papel para o Zn no cérebro é na neurotransmissão por meio das sinapses glutamatérgicas (Crouch et al, 2007;Donnelly et al, 2007). As sinapses glutamérgicas, onde a patologia amilóide se inicia na DA, contém altas concentrações de Zn, que é liberado durante a neurotransmissão (Crouch et al, 2007).…”

Section: Zinco Na Doença De Alzheimerunclassified

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Determinação de elementos traço no encéfalo de idosos em diferentes estados cognitivos

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Die Alzheimer‐Demenz: von der Pathologie zu therapeutischen Ansätzen

Jakob‐Roetne

Jacobsen

2009

Angewandte Chemie

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Die gegenwärtigen Strategien zur Entwicklung von Alzheimer‐Therapien sind breit gefächert. Ein verstärktes Augenmerk gilt der Suche nach Hemmstoffen (siehe Bild für zwei Beispiele) der proteolytischen Enzyme β‐ und γ‐Secretase, die die Spaltung des Amyloid‐Vorläuferproteins in Amyloid‐β‐Peptide inhibieren, aus denen die krankheitstypischen Plaque‐Ablagerungen im Gehirn von Alzheimer‐Patienten entstehen.magnified imageDie Forschungen über Altersdemenz und die Alzheimersche Krankheit umfassen ein sehr breites Feld wissenschaftlicher Aktivitäten. So wurden etwa bei der letztjährigen internationalen Tagung der Alzheimer‐Gesellschaft (ICAD 2008 in Chicago) mehr als 2200 Einzelbeiträge präsentiert. Ziel dieses Aufsatzes ist es, einen zusammenhängenden Überblick über das Gebiet zu präsentieren und die wichtigsten Themen und Forschungstrends aufzuzeigen. Die Ausführungen beginnen mit einer Diskussion von Verhaltensabweichungen und sichtbaren pathologischen Befunden, bevor dann auf die molekularen Details der Pathologie eingegangen wird. Besonderes Augenmerk gilt der “Amyloidhypothese” der Alzheimer‐Krankheit, da sie das theoretische Fundament für die meisten der in der Entwicklung befindlichen therapeutischen Konzepte bildet.

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The modulation of metal bio‐availability as a therapeutic strategy for the treatment of Alzheimer's disease

Cited by 70 publications

References 86 publications

Substoichiometric Levels of Cu2+ Ions Accelerate the Kinetics of Fiber Formation and Promote Cell Toxicity of Amyloid-β from Alzheimer Disease

Substoichiometric Levels of Cu2+ Ions Accelerate the Kinetics of Fiber Formation and Promote Cell Toxicity of Amyloid-β from Alzheimer Disease

Determinação de elementos traço no encéfalo de idosos em diferentes estados cognitivos

Die Alzheimer‐Demenz: von der Pathologie zu therapeutischen Ansätzen

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