Rescue of zinc ion trapping by Amyloid Beta using novel Zn2+ loaded nanoparticles

Homeostasis of metal ions such as Zn2+ is essential for proper brain function. The list of psychiatric and neurodegenerative disorders involving a dysregulation of brain Zn2+-levels is long and steadily growing, including Alzheimer’s disease (AD). Thus, the possibility of altering Zn2+-levels within the brain is emerging as a new target for the prevention and treatment of neurological diseases. Here, we show results focusing on mechanisms of synapse formation, maturation and signaling at excitatory post-synapses mediated by ProSAP/Shank proteins. ProSAP2/Shank3 is dependent on local concentrations of Zn2+ and the presence of Amyloid Beta (Abeta) that is able to bind Zn2+ leads to a deregulation of ProSAP2/Shank3 as a result of Zn2+ sequestration by Abeta. Zn2+ can induce Abeta monomers to aggregate in different forms and is known to bind Abeta via its histidine imidazole rings and accumulate within senile plaques. The addition of Zn2+ could rescue the effects induced by Abeta on synaptic density and PSD platform formation. Thus, it might be possible that Abeta causes cognitive impairment by trapping synaptic Zn2+ rather than through direct toxicity and that a local and controlled increase of the Zn2+ concentration in the brain might be a promising future to influence and investigate the pathology of AD. However, zinc ions cannot cross the blood brain barrier and therefore, new technologies are necessary to manipulate brain Zn2+ levels. Therefore, we encapsulated zinc ions in Nanoparticles (NPs), releasing their cargo over time and able to cross the blood-brain barrier (BBB). Using these NPs, we were able to increase the intracellular Zn2+ concentration of target cells. It was shown that NPs associate with cells and are taken up via endocytosis before they degrade over time. These NPs were further modified in order to preferentially target specific neuronal cell populations.