Selective Intracellular Release of Copper and Zinc Ions from Bis(thiosemicarbazonato) Complexes Reduces Levels of Alzheimer Disease Amyloid-β Peptide

Donnelly, Paul S.; Caragounis, Aphrodite; Du, Tai; Laughton, Katrina; Volitakis, Irene; Cherny, Robert A.; Sharples, Robyn A.; Hill, Andrew F.; Li, Qiao‐Xin; Masters, Colin L.; Barnham, Kevin J.; White, Anthony R.

doi:10.1074/jbc.m705957200

Cited by 185 publications

(208 citation statements)

References 34 publications

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“…Importantly, once Cu II (gtsm) is exposed to the intracellular reducing environment, Cu II is reduced to Cu I , causing it to dissociate from the ligand and to increase Cu bioavailability. The negative control Cu II (atsm) does not reduce and dissociate under normal intracellular conditions, and therefore does not increase Cu bioavailability (18,(23)(24)(25)(26). We found both metal complexes increased cellular Cu levels several hundredfold ( Fig.…”

Section: Resultsmentioning

confidence: 75%

“…A␤ has strong] inhibitory potential toward hippocampal long-term potentiation (LTP) (7,27), and metal complex-mediated activation of neuroprotective pathways can decrease A␤ levels in vitro (17,18,20). Therefore, we determined whether Cu II (gtsm) was able to rescue A␤-induced inhibition of LTP.…”

Section: Resultsmentioning

confidence: 99%

“…These data demonstrate that increased bioavailability of intracellular Cu rather than elevated cellular Cu per se is required to induce cellular pathways that lead to increased GSK3␤ phosphorylation at ser9 (i.e., GSK3␤ inhibition). We have shown previously that induction of these cellular pathways using metal complexes leads to decreased levels of A␤ in cell cultures because of increased expression of A␤-degrading proteases (17,18,20).…”

Section: Resultsmentioning

confidence: 99%

“…Its clinical application was developed based on the potential to inhibit A␤ toxicity through modulation of A␤-metal interactions (13)(14)(15)(16), but the in vivo mechanism of action for PBT2 still requires elucidation. Cell culture studies have provided mechanism of action data to show that membrane-permeable compounds with the potential to form metal complexes, such as PBT2, can inhibit A␤ toxicity by increasing cellular metal ion bioavailability and activating neuroprotective cell signaling pathways (17)(18)(19)(20). Central to these pathways is inhibition of glycogen synthase kinase 3␤ (GSK3␤).…”

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confidence: 99%

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Increasing Cu bioavailability inhibits Aβ oligomers and tau phosphorylation

Crouch

Hung²,

Adlard³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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248

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Cognitive decline in Alzheimer's disease (AD) involves pathological accumulation of synaptotoxic amyloid-␤ (A␤) oligomers and hyperphosphorylated tau. Because recent evidence indicates that glycogen synthase kinase 3␤ (GSK3␤) activity regulates these neurotoxic pathways, we developed an AD therapeutic strategy to target GSK3␤. The strategy involves the use of copper-bis(thiosemicarbazonoto) complexes to increase intracellular copper bioavailability and inhibit GSK3␤ through activation of an Akt signaling pathway. Our lead compound Cu II (gtsm) significantly inhibited GSK3␤ in the brains of APP/PS1 transgenic AD model mice. Cu II (gtsm) also decreased the abundance of A␤ trimers and phosphorylated tau, and restored performance of AD mice in the Y-maze test to levels expected for cognitively normal animals. Improvement in the Y-maze correlated directly with decreased A␤ trimer levels. This study demonstrates that increasing intracellular copper bioavailability can restore cognitive function by inhibiting the accumulation of neurotoxic A␤ trimers and phosphorylated tau.Alzheimer's disease ͉ bioinorganic chemistry ͉ glycogen synthase kinase ͉ therapeutic ͉ animal model A lzheimer's disease (AD) is a neurodegenerative disorder characterized clinically by impaired cognitive performance and pathologically by cerebral deposition of extracellular amyloid plaques and intracellular neurofibrillary tangles. Amyloid plaques in AD contain aggregated forms of the 39-to 43-aa amyloid-␤ peptide (A␤) and A␤ is strongly implicated as a causative agent responsible for cognitive failure in AD. A diverse range of mechanisms for A␤ toxicity has been reported (1). A␤ is produced from the amyloid precursor protein (APP) (2-5) and readily aggregates to form insoluble, high-molecular-mass amyloid structures. Intermediates on the A␤ aggregation pathway, primarily low-molecular-mass oligomers such as dimers and trimers, exhibit the greatest neurotoxicity (6-8). In addition to A␤ oligomers, aberrantly phosphor ylated microtubuleassociated protein tau is also associated with cognitive decline in AD (9). Intracellular neurofibrillary tangles in the AD brain contain hyperphosphorylated tau, and A␤ induced cognitive deficits characteristic of AD transgenic mice are attenuated by decreasing levels of endogenous tau (10).It is now widely recognized that a truly effective therapeutic compound for treating AD needs to attenuate both the A␤-and tau-mediated pathologies. Recent positive outcomes for PBT2 in clinical and preclinical trials are therefore pertinent. Lannfelt et al.(11) demonstrated in phase IIa clinical trials that PBT2 lowers plasma A␤ levels and attenuates cognitive decline, and Adlard et al. (12) have shown that PBT2 decreases interstitial A␤ and phosphorylated tau in the brains of AD model mice. PBT2 is a secondgeneration 8-OH quinoline, which, unlike its predecessor clioquinol, lacks iodine and was selected for clinical development because of its easier chemical synthesis, higher solubility, and increased blood-brain barrier perme...

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Section: Resultsmentioning

confidence: 75%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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Increasing Cu bioavailability inhibits Aβ oligomers and tau phosphorylation

Crouch

Hung²,

Adlard³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

248

268

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“…The coppercontaining bis(thiosemicarbazone) compound Cu II GTSM, has been shown to lower Aβ levels, GSK3β activity, and phosphorylated tau levels in cell culture and APP/PS1 transgenic mice [194,219], which accompanied improved cognition in the Y-maze assay. A related compound, Cu II ATSM, was not beneficial to the APP/PS1 transgenic model of AD, but conferred neuroprotection in 4 animal models of PD [220], which is also complicated by copper deficiency [168].…”

Section: Bis(thiosemicarbazone) Ligandsmentioning

confidence: 99%

Biometals and Their Therapeutic Implications in Alzheimer's Disease

2015

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No disease modifying therapy exists for Alzheimer's disease (AD). The growing burden of this disease to our society necessitates continued investment in drug development. Over the last decade, multiple phase 3 clinical trials testing drugs that were designed to target established disease mechanisms of AD have all failed to benefit patients. There is, therefore, a need for new treatment strategies. Changes to the transition metals, zinc, copper, and iron, in AD impact on the molecular mechanisms of disease, and targeting these metals might be an alternative approach to treat the disease. Here we review how metals feature in molecular mechanisms of AD, and we describe preclinical and clinical data that demonstrate the potential for metal-based drug therapy.

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Copper in Brain and Neurodegeneration

Liddell

Bush

White

2004

Encyclopedia of Inorganic and Bioinorganic Chemistry

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Cu is an essential element for the brain. It is involved in neurotransmission and is required for several cuproenzymes of the brain. Cu deficiency and Cu excess are associated with Menkes disease and Wilson's disease, respectively, and the importance of Cu in the brain is amply illustrated by the severe neurological symptoms elicited by these diseases. Disruption of Cu homeostasis is also evident in complex neurodegenerative diseases and is implicated in their pathogenesis. Cu influences the regulation and aggregation of key Alzheimer's disease ( AD ) neuropathological proteins such as amyloid precursor protein, amyloid‐β, and tau. Parkinson's disease ( PD ) is associated with a decreased Cu content of the substantia nigra, the brain region that is affected in the disease. Cu also promotes the aggregation of α‐synuclein, the predominant protein present in the characteristic Lewy bodies of PD brain, and huntingtin, found in inclusions in Huntington's disease. Mutant SOD1 is thought to have a toxic gain of function in amyotrophic lateral sclerosis, possibly caused by Zn‐deficient CuSOD1 . Niemann‐Pick type C disease ( NPC ) is caused by mutations in the NPC gene, giving rise to impaired NPC protein. Evidence suggests that NPC may be involved in Cu metabolism. The involvement of Cu in these diseases is highlighted by the efficacy of therapeutics targeting the redistribution of Cu. Cu ionophores such as clioquinol and PBT2 bind endogenous Cu, transport it into cells and induce multiple cellular pathways. In AD , these ionophores likely sequester Cu bound to amyloid‐β plaques. Preformed bis(thiosemicarbazone)‐Cu complexes deliver exogenous Cu into the brain and induce similar pathways to the ionophores. These Cu complexes have shown efficacy in animal models of several neurodegenerative diseases, and the cellular pathways induced are being elucidated. These therapeutic outcomes, together with improved resolution of techniques for identifying Cu distribution in brain cells, are providing valuable new insights into the role of Cu in neuronal and glial cell homeostasis.

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Selective Intracellular Release of Copper and Zinc Ions from Bis(thiosemicarbazonato) Complexes Reduces Levels of Alzheimer Disease Amyloid-β Peptide

Cited by 185 publications

References 34 publications

Increasing Cu bioavailability inhibits Aβ oligomers and tau phosphorylation

Increasing Cu bioavailability inhibits Aβ oligomers and tau phosphorylation

Biometals and Their Therapeutic Implications in Alzheimer's Disease

Copper in Brain and Neurodegeneration

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