Dietz_2024_Mol.Neurobiol__

The most common cause of dementia among elderly people is Alzheimer's disease (AD). The typical symptom of AD is the decline of cognitive abilities, which is caused by loss of synaptic function. Amyloid-beta (Abeta) oligomers play a significant role in the development of this synaptic dysfunction. Neuroligin-(NL)1 is a postsynaptic cell-adhesion molecule located in excitatory synapses and involved in the maintenance and modulation of synaptic contacts. A recent study has found that Abeta interacts with the soluble N-terminal fragment of NL1. The present study aimed to elucidate the role of NL1 in Abeta-induced neuropathology. Employing surface plasmon resonance and competitive ELISA, we confirmed the high-affinity binding of NL1 to the Abeta peptide. We also identified a sequence motif representing the NL1-binding site for the Abeta peptide and showed that a synthetic peptide modeled after this motif, termed neurolide, binds to the Abeta peptide with high affinity, comparable to the NL1-Abeta interaction. To assess the effect of neurolide in vivo, wild-type and 5XFAD mice were subcutaneously treated with this peptide for 10 weeks. We observed an increase in Abeta plaque formation in the cortex of neurolide-treated 5XFAD mice. Furthermore, we showed that neurolide reduces the activity of neprilysin, the predominant Abeta-degrading enzyme in the brain. Accordingly, we suggest that neurolide is the NL1-binding site for Abeta peptide, and acts as an inhibitor of neprilysin activity. Based on these data, we confirm the involvement of NL1 in the development of AD and suggest a mechanism for NL1-induced Abeta plaque formation.