Subcellular Localization of Copper—Cellular Bioimaging with Focus on Neurological Disorders

Abstract

As an essential trace element, copper plays a pivotal role in physiological body functions. In fact, dysregulated copper homeostasis has been clearly linked to neurological disorders including Wilson and Alzheimer’s disease. Such neurodegenerative diseases are associated with progressive loss of neurons and thus impaired brain functions. However, the underlying mechanisms are not fully understood. Characterization of the element species and their subcellular localization is of great importance to uncover cellular mechanisms. Recent research activities focus on the question of how copper contributes to the pathological findings. Cellular bioimaging of copper is an essential key to accomplish this objective. Besides information on the spatial distribution and chemical properties of copper, other essential trace elements can be localized in parallel. Highly sensitive and high spatial resolution techniques such as LA-ICP-MS, TEM-EDS, S-XRF and NanoSIMS are required for elemental mapping on subcellular level. This review summarizes state-of-the-art techniques in the field of bioimaging. Their strengths and limitations will be discussed with particular focus on potential applications for the elucidation of copper-related diseases. Based on such investigations, further information on cellular processes and mechanisms can be derived under physiological and pathological conditions. Bioimaging studies might enable the clarification of the role of copper in the context of neurodegenerative diseases and provide an important basis to develop therapeutic strategies for reduction or even prevention of copper-related disorders and their pathological consequences.

Copper Toxicity Links to Pathogenesis of Alzheimer’s Disease and Therapeutics Approaches

“…A recent study suggested that the direct transfer of copper from Ctr1 to chaperones and then passing it to SOD1 is via forming a Ctr1-CCS-SOD1 complex [ 218 ]. Besides CCS, soluble copper chaperones such as Atox1 and Cox17 can also escort Cu + from Ctr1 in the cytosolic pool to facilitate copper supply to their specific target compartments [ 220 ].…”

A matter of concern – Trace element dyshomeostasis and genomic stability in neurons

“…Besides increasing the complexity of model systems, studies should focus more on intracellular bioavailability data to strengthen their hypothesis regarding the direct influence of the TEs taken into account on enzymes, proteins, and subcellular structures. In this context, the current research area of novel methods to determine subcellular metal localisation like the nano secondary ion mass spectrometry offer a great potential [ 188 ].…”

Rutin ameliorates copper sulfate‐induced brain damage via antioxidative and anti‐inflammatory activities in rats

“…[ 8,9 ] Although Cu has so many functions in biological systems, its concentration must be appropriately regulated to avoid toxicity. [ 10‐12 ] Excess Cu in the biological system has been linked to the generation of reactive oxygen species via the Fenton reaction [ 13,14 ] and associated with oxidative stress in the brain and neuronal damage. [ 15,16 ] Cu toxicity may be due to its ability to exist in either the stable (Cu 2+) or unstable (Cu + ) state.…”

“…Increased Cu concentration is associated with damages, including neurotoxicity [ 22 ] and neurological conditions such as Alzheimer's disease (AD), [ 23,24 ] Parkinson's disease, Menke's disease, Wilson's disease, and so forth. [ 1,11,25,26 ] For instance, studies revealed that Cu imbalance has widely affected the functions of neurons and may lead to cognitive deficits and AD pathology. [ 27 ] Also, it has been established that Cu accumulates in the amyloid β plaque of patients with AD.…”