Mapping Brain Metals to Evaluate Therapies for Neurodegenerative Disease

Abstract

The brain is rich in metals and has a high metabolic rate, making it acutely vulnerable to the toxic effects of endogenously produced free radicals. The abundant metals, iron and copper, transfer single electrons as they cycle between their reduced (Fe 2+ , Cu 1+ ) and oxidized (Fe 3+ , Cu 2+ ) states making them powerful catalysts of reactive oxygen species (ROS) production. Even redox inert zinc, if present in excess, can trigger ROS production indirectly by altering mitochondrial function. While metal chelators seem to improve the clinical outcome of several neurodegenerative diseases, their mechanisms of action remain obscure and the effects of long-term use are largely unknown. Most chelators are not specific to a single metal and could alter the distribution of multiple metals in the brain, leading to unexpected consequences over the long-term. We show here how X-ray fluorescence will be a valuable tool to examine the effect of chelators on the distribution and amount of metals in the brain.

A novel approach to quantify different iron forms in ex-vivo human brain tissue

“…Loosely bound iron should be less than 5% of the total iron within cells59. Total iron levels in healthy aged subjects vary from 122  μg / g 62 (middle temporal gyrus) to 28  μg / g 27 (temporal cortex): therefore we would expect to measure iron concentrations in the range of 6.1–1.4  μg / g . Our method derives values of 1.9 ± 0.4  μg / g and 2.1 ± 0.4  μg / g Fe(III) ions for the HC and AD patient, respectively, in agreement with the expectations.…”

Synchrotron Radiation X-Ray Microfluorescence Reveals Polarized Distribution of Atomic Elements during Differentiation of Pluripotent Stem Cells

“…Cu is a metallic element and is deeply involved in neural tissue activity [32] due to its high ability in transferring single electrons. These data suggest that metal accumulation could be an early event in neural differentiation, triggered in neural progenitor cells.…”

Zinc-mediated Allosteric Inhibition of Caspase-6

“…The underlying physiological reason as to why caspases evolved to bind zinc is not entirely clear, but we speculate that the native affinity of a cysteine-histidine dyad requires an appropriate response in a zinc-rich environment. Caspase-6, in particular, is known to play a role in cells and tissues with extremely high zinc concentrations (38,39), so perhaps it was essential that caspase-6 evolve mechanisms to respond to these conditions. Beyond this, why caspase-6 should be subject to allosteric inhibition by zinc remains somewhat unclear.…”

“…We note that these differences may be due to the size of the substrates used, as a small tetrapeptide (VEID) binds locally only in the active site, whereas a protein substrate (299 amino acids) may make contact with other regions of the caspase-6 enzyme (54). Although the K i is in the high nanomolar range, this may in fact be biologically relevant, as the zinc concentration in brain tissue, which is where caspase-6 plays its critical roles in neurodegeneration, can be in the millimolar range (38,39).…”

“…Mounting evidence suggests that zinc is involved in a variety of neurological diseases (37). Zinc is found at extremely high concentrations in brain lesions (plaque rim, 1024 M; plaque core, 1327 M; senile plaque, 1055 M, and Alzheimer neuropil, 786 M) (38,39). Zinc accumulation in brain is a prominent feature of advanced Alzheimer disease and is biochemically linked to amyloid-␤ accumulation and dementia severity.…”