Changes in uptake of vitamin B12 and trace metals in brains of mice treated with clioquinol

Yassin, Mohammed S.; Ekblom, Jonas; Xilinas, Michel; Gottfries, C. G.; Oreland, Lars

doi:10.1016/s0022-510x(99)00297-x

Cited by 120 publications

(86 citation statements)

References 17 publications

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“…Iron, cobalt, and manganese levels were unaltered (33). In NTg mice, clioquinol treatment decreases copper, iron, and cobalt levels (57). In light of our current findings, this paradoxical increase in copper and zinc in clioquinol-treated Tg2576 mice may be explained by clioquinol preventing Cu 2ϩ and Zn 2ϩ from complexing with extracellular A␤, so securing metal for uptake into metal-deficient brain tissue instead of being sequestered into amyloid.…”

Section: Discussionmentioning

confidence: 42%

Overexpression of Alzheimer's Disease Amyloid-β Opposes the Age-dependent Elevations of Brain Copper and Iron

Maynard¹,

Cappai²,

Volitakis³

et al. 2002

Journal of Biological Chemistry

335

307

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Section: Discussionmentioning

confidence: 42%

Overexpression of Alzheimer's Disease Amyloid-β Opposes the Age-dependent Elevations of Brain Copper and Iron

Maynard¹,

Cappai²,

Volitakis³

et al. 2002

Journal of Biological Chemistry

335

307

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“…In the present work we have successfully developed a [ (Hannibal et al, 2008;Mellman et al, 1978;Yamani et al, 2008;Yassin et al, 2000;Youngdahl-Turner et al, 1978) or aspects of lysosome function in cells and mice (Manunta et al, 2007;Yang et al, 2011). Our data and in mouse models of ageing and neurodegenerative disease.…”

Section: Discussionmentioning

confidence: 95%

Analysis of subcellular [57Co] cobalamin distribution in SH-SY5Y neurons and brain tissue

Zhao¹,

Ruberu²,

Li³

et al. 2013

Journal of Neuroscience Methods

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Cobalamin (Cbl) utilization as a cofactor for methionine synthase and methylmalonyl-CoA mutase is dependent on the transport of Cbl through lysosomes and its subsequent delivery to the cytosol and mitochondria. We speculated that neuropathological conditions that impair lysosomal function (e.g., agerelated lipofuscinosis and specific neurodegenerative diseases) might impair lysosomal Cbl transport. To address this question, an appropriate method to quantify intracellular Cbl transport in neuronal cell types and brain tissue is required. Thus, we developed methods to measure [ 57 Co] Cbl levels in lysosomes, mitochondria and cytosol obtained from in vitro and in vivo sources. Human SH-SY5Y neurons or HT1080 fibroblasts were labeled with [ 57 Co] Cbl and homogenized using a ball-bearing homogenizer, and the lysates were separated into 10 fractions using ultracentrifugation in an OptiPrep density gradient. Lysosomes were recovered from the top of the gradient (fractions 1-5), which were clearly separated from mitochondria (fractions 7-9) on the basis of the expression of the marker proteins, LAMP2 and VDAC1. The isolated lysosomes were intact based on their colocalization with acid phosphatase activity. The lysosomal and mitochondrial fractions were free of the cytosolic markers beta-actin and methionine synthase. The relative distribution of [ 57 Co] Cbl in both neurons and fibroblasts was as follows: 6% in the lysosomes, 14% in the mitochondria and 80% in the cytosol. This technique was also used to fractionate organelles from mouse brain, where marker proteins were detected in the gradient at positions similar to those observed for the cell lines, and the relative distribution of [ 57 Co] Cbl was as follows: 12% in the lysosomes, 15% in the mitochondria and 73% in the cytosol. These methods provide a useful tool for the investigation of intracellular Cbl trafficking in a neurobiological setting. fractions using ultracentrifugation on an OptiPrep density gradient. Lysosomes were recovered at the top of the gradient (fractions 1 to 5) and were clearly separated from mitochondria (fractions 7 to 9) based on marker proteins LAMP2 and VDAC1, respectively.The isolated lysosomes were intact based on colocalisation with acid phosphatase activity.The lysosomal and mitochondrial fractions were free of cytosolic markers beta-actin and methionine synthase.

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“…The mechanism of this toxicity has not been precisely defined. The current leading hypothesis is that clioquinol decreases cobalamin (vitamin B 12 ) bioavailability, resulting in a deficiency state and a syndrome similar to subacute combined degeneration (69). However, it was reported that, given safely under the conditions of controlled dosing and vitamin supplementation, episodes of subacute myelo-opticoneuropathy may be avoided (63).…”

Section: Metals Chelators For the Treatment Of Alzheimer's Diseasementioning

confidence: 99%

Metal ions, Alzheimer's disease and chelation therapy

Budimir¹

2011

Acta Pharmaceutica

168

110

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Alzheimer's disease (AD) is a progressive and fatal neurodegenerative disease, clinically characterized by memory and cognitive dysfunctions. It is primarily a disease of old age (1) and is the most prevalent cause of dementia in elderly people (2). AD affects about 35 million people worldwide today (3) and it is estimated to nearly double every 20 years, to reach 66 million in 2030, and 115 million in 2050 (3). There is no known cause and no cure for AD and these numbers makes finding a cure or rational treatment for AD an urgent priority. Despite significant advances in understanding the neuropathological and neurochemical events taking place in AD, the etiopathogenesis of progressive and mental cognitive dysfunction associated with aging remains largely unclear.Pathologically, AD is characterized by neuronal degeneration. The brains of AD patients are mainly characterized by extracellular proteic (or neuritic) deposits (amyloid or senile plaques) surrounded by dystrophic neuritic and intracellular neurofibrillary tangles (NFT) (4). The plaques and tangles are present mainly in brain regions involved in learning and memory and emotional behavior such as the entorhinal cortex, hippocam- In the last few years, various studies have been providing evidence that metal ions are critically involved in the pathogenesis of major neurological diseases (Alzheimer, Parkinson). Metal ion chelators have been suggested as potential therapies for diseases involving metal ion imbalance. Neurodegeneration is an excellent target for exploiting the metal chelator approach to therapeutics. In contrast to the direct chelation approach in metal ion overload disorders, in neurodegeneration the goal seems to be a better and subtle modulation of metal ion homeostasis, aimed at restoring ionic balance. Thus, moderate chelators able to coordinate deleterious metals without disturbing metal homeostasis are needed. To date, several chelating agents have been investigated for their potential to treat neurodegeneration, and a series of 8-hydroxyquinoline analogues showed the greatest potential for the treatment of neurodegenerative diseases.

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Changes in uptake of vitamin B12 and trace metals in brains of mice treated with clioquinol

Cited by 120 publications

References 17 publications

Overexpression of Alzheimer's Disease Amyloid-β Opposes the Age-dependent Elevations of Brain Copper and Iron

Overexpression of Alzheimer's Disease Amyloid-β Opposes the Age-dependent Elevations of Brain Copper and Iron

Analysis of subcellular [57Co] cobalamin distribution in SH-SY5Y neurons and brain tissue

Metal ions, Alzheimer's disease and chelation therapy

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