Inhibiting AP2M1-mediated GluA2 endocytosis by G2CT peptide ameliorates synaptic and memory deficits in Alzheimer's...

Abnormal endocytosis of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) subunit GluA2 is implicated in early synaptic dysfunction in Alzheimer's disease (AD). In this study, we utilized human brain tissue samples from both male and female autopsy specimens (including 6 clinically diagnosed AD patients and 6 normal controls without central nervous system pathology), male and female 5 × FAD five-transgenic mice and their wild-type (WT) littermates (C57BL/6J genetic background), as well as mouse neuroblastoma Neuro-2a (N2A) cells, to demonstrate that GluA2 undergoes enhanced endocytosis in APP-overexpressing N2A cells. This enhanced endocytosis is driven by an increased interaction with the μ subunit of the adaptor protein complex 2 (AP2M1), without affecting total GluA2 protein levels. Targeting this interaction with the competitive peptide G2CT effectively restores GluA2 membrane expression and improves synaptic function in vivo. Furthermore, G2CT rescues cognitive deficits in male and female 5 × FAD AD mouse models, without detectable alterations in amyloid precursor protein processing or amyloid-beta (Aβ) production under the experimental conditions used. These findings identify the GluA2-AP2M1 interaction as a critical mechanism of early synaptic dysfunction and highlight a therapeutic strategy for AD that acts downstream of amyloid-β signaling and ameliorates synaptic and cognitive deficits without altering amyloid pathology.