Endogenous Pigment Mimicking Engineered Nanovesicle Targets Extrasynaptic NMDA Receptors against Ca2+-Mediated Excitotoxicity in Alzheimer’s Disease

In Alzheimer's disease (AD), deposition of toxic Aβ42 oligomers causes excessive internalization of 2A subunit dominant NMDA receptors (GluN2A subtype) from the synaptic region. This causes a significant reduction of the synaptic glutamate interaction site. The absence of GluN2A propagates spillage of glutamate to the extrasynaptic space, where it interacts with the 2B subunit dominant NMDA receptor (GluN2B subtype). This interaction causes excessive Ca²⁺ influx and perturbation of autophagy, thus disrupting mitochondrial membrane potential and producing reactive oxygen species, causing neuronal death. In this context, our hypothesis suggests that selective inhibition of extrasynaptic GluN2B receptors could produce multifaceted outcomes against AD. Our aim is to devise a neuromelanin mimicking nanovesicle, particularly targeting extrasynaptic GluN2B. A conceptualized nanovesicle is designed to be larger than the synaptic cleft space (>100 nm) with the decoration of novel GluN2B targeting peptides. Therefore, we envision that this engineered nanomaterial will only inhibit the extrasynaptic GluN2B-mediated Ca²⁺ excitotoxicity and also revive homeostatic autophagy.