Evidence for release of copper in the brain: Depolarization‐induced release of newly taken‐up ⁶⁷copper

Abstract

The potential importance of copper (Cu) in neurosecretion can be inferred from the demonstration that extracellular Cu modulates the secretory function of peptidergic neurons (in vitro studies) and from the presence of high Cu concentrations in nerve terminals and secretory vesicles, primarily within the soluble matrix of the latter. We have previously hypothesized that vesicular Cu is released from neurons undergoing exocytosis and that such extracellular Cu plays an important modulatory role in the central nervous system. To test this Cu release hypothesis, rat hypothalami were incubated under in vitro conditions for 1 or 2 hr with 20 nM radiolabeled Cu (67Cu), and then 67Cu release was stimulated by a depolarizing concentration (60 mM) of K+. K+ markedly (P less than 0.001) stimulated 67Cu release in a Ca2+-dependent manner (stimulated release was 95 fmol/10 min/mg protein after 1 hr 67Cu loading and 160 after 2 hr). These amounts of released 67Cu account for about 10% of the total 67Cu taken up by the tissue. These results indicate that part of the 67Cu taken up by hypothalamic explants is directed into an intracellular compartment from where it can be released by a Ca2+-dependent mechanism, thus providing strong support to our hypothesis that release of copper is operative in situ in the brain.

Truncated Amyloid-β(11–40/42) from Alzheimer Disease Binds Cu2+ with a Femtomolar Affinity and Influences Fiber Assembly

“…This has ramifications for the ability of A␤ (11-40/42) to compete for Cu 2ϩ ions at the synapse. Cu 2ϩ is released at the synapse during neuronal depolarization and is thought to reach levels between 15 and 200 M (38). CSF levels of Cu 2ϩ are lower, at 500 nM, (72), but the femtomolar affinity of A␤ (11-40/42) will readily bind Cu 2ϩ even at these lower concentrations.…”

Structural characterization of copper(II) binding to α-synuclein: Insights into the bioinorganic chemistry of Parkinson's disease

“…We propose that the concentrations of Cu(II) in neurons and glia are sufficient to contribute to potential abnormal interaction with proteins such as AS under certain adverse circumstances. Furthermore, although the metabolic pathways of extracellular Cu(II) are poorly understood, Cu(II) levels as high as 15 M can be envisioned (50), sufficient to form complexes with extracellular targets implicated in diseases such as A␤. Although more studies are needed to explore other biological aspects of Cu(I-I)-AS interactions, the structural features emerging from this work indicate that perturbations in copper metabolism may constitute a more widespread element in neurodegenerative disorders than has been recognized previously.…”

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

“…Brain coppper concentration is related to plasma copper concentration (51), and both plasma (52,53) and CSF (54) copper levels are significantly elevated in AD. Taken together, these findings imply that there is a pooling of extracellular copper, and a deficiency of intracellular copper, in the AD brain.…”