Next-generation Cu(II) selective peptide shuttles prevent Cu(Aβ)-induced toxicity and microglial activation in organotypic hippocampal slices

Alzheimers disease (AD) remains the most prevalent neurodegenerative disease with hallmarks including the apparition, in specific areas of the brain, of intracellular neurofibrillary tangles and extracellular amyloid plaques. The latter result from an abnormal metabolism of Amyloid-β precursor protein (APP) leading to its accumulation in plaques. Ex vivo analysis of AD patients brains, show an abnormally elevated concentration of metals including Cu, Zn and Fe in these plaques. Some studies have also demonstrated altered Cu levels in the entire brain and more specifically in regions heavily affected in AD. These modifications are often accompanied by a decline in neuronal Cu levels and by an increase in the proportion of extracellular labile Cu, which in turn promotes reactive oxygen species formation. To correct this Cu dyshomeostasis, we designed and synthesized novel Cu(II)-selective peptide shuttles, capable of swiftly retrieving Cu from extracellular Amyloid-β and subsequently transporting and releasing Cu inside cells. We demonstrate here the capacity of this new Cu-shuttles, DapHH-aR5W4NBD and HDapH-aR5W4NBD, to protect organotypic hippocampal slices (OHSCs) from Cu(Aβ)-induced insult and their capability to rescues Cu-induced microglial activation and proliferation.