SorCS1 inhibits amyloid-β binding to neurexin and rescues amyloid-β-induced synaptic pathology.

ABSTRACT: Amyloid-β oligomers (AβOs), toxic peptide aggregates found in Alzheimer's disease, cause synapse pathology. AβOs interact with neurexins (NRXs), key synaptic organizers, and this interaction dampens normal trafficking and function of NRXs. Axonal trafficking of NRX is in part regulated by its interaction with SorCS1, a protein sorting receptor, but the impact of SorCS1 regulation of NRXs in Aβ pathology was previously unstudied. Here, we show competition between the SorCS1 ectodomain and AβOs for β-NRX binding and rescue effects of the SorCS1b isoform on AβO-induced synaptic pathology. Like AβOs, the SorCS1 ectodomain binds to NRX1β through the histidine-rich domain of NRX1β, and the SorCS1 ectodomain and AβOs compete for NRX1β binding. In cultured hippocampal neurons, SorCS1b colocalizes

SUBMITTER: Lee AK 

PROVIDER: S-EPMC9880023 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature