Copper: from neurotransmission to neuroproteostasis

Abstract

Copper is critical for the Central Nervous System (CNS) development and function. In particular, different studies have shown the effect of copper at brain synapses, where it inhibits Long Term Potentation (LTP) and receptor pharmacology. Paradoxically, according to recent studies copper is required for a normal LTP response. Copper is released at the synaptic cleft, where it blocks glutamate receptors, which explain its blocking effects on excitatory neurotransmission. Our results indicate that copper also enhances neurotransmission through the accumulation of PSD95 protein, which increase the levels of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors located at the plasma membrane of the post-synaptic density. Thus, our findings represent a novel mechanism for the action of copper, which may have implications for the neurophysiology and neuropathology of the CNS. These data indicate that synaptic configuration is sensitive to transient changes in transition metal homeostasis. Our results suggest that copper increases GluA1 subunit levels of the AMPA receptor through the anchorage of AMPA receptors to the plasma membrane as a result of PSD-95 accumulation. Here, we will review the role of copper on neurotransmission of CNS neurons. In addition, we will discuss the potential mechanisms by which copper could modulate neuronal proteostasis (“neuroproteostasis”) in the CNS with focus in the Ubiquitin Proteasome System (UPS), which is particularly relevant to neurological disorders such as Alzheimer’s disease (AD) where copper and protein dyshomeostasis may contribute to neurodegeneration. An understanding of these mechanisms may ultimately lead to the development of novel therapeutic approaches to control metal and synaptic alterations observed in AD patients.

Retained executive abilities in mild cognitive impairment are associated with increased white matter network connectivity

“…Decreased FA in a number of tracts has been shown to be a marker of AD dementia, relating changes in diffusive properties of white matter to impairment in AD dementia [20]. FA has been shown to be less sensitive to the early changes of mild cognitive impairment [21]; however, the significant differences that we found in FA between those with high and executive abilities suggests that FA changes in MCI may be related to executive deficits [22]. Our study confirms that the white matter changes found previously in AD may manifest earlier as a function of diminished executive abilities in MCI, and that these diminished abilities are likely to accompany early white matter changes in specific white matter tracts.…”

The Inorganic Side of NGF: Copper(II) and Zinc(II) Affect the NGF Mimicking Signaling of the N-Terminus Peptides Encompassing the Recognition Domain of TrkA Receptor

“…Several new therapeutic strategies are currently aimed at regulating and restoring metal homeostasis (Opazo et al, 2014; Bharti et al, 2016). Interestingly, also four neurotrophic factor, namely BDNF, CNTF, PEDF, GDNF, have been reported to increase the intracellular Zn level in RPE (retinal pigmental epithelium) cells, modulating the expression of zinc transporters which increase zinc uptake (Leung et al, 2008).…”

Copper signaling in the brain and beyond

“…For detailed discussions of the role of copper in neurobiology, the reader is referred to recent reviews by D'Ambrossi and Rossi (55), Gaier, Eipper and Mains (56), and Opazo, Greenough and Bush (57). While neurobiology has long hinted at the prospects of copper signaling, the identification and study of copper signaling in other tissues with more detailed study of specific molecular targets is rapidly expanding.…”