PT  - JOURNAL ARTICLE
AU  - Alfred Kihoon Lee
AU  - Nayoung Yi
AU  - Husam Khaled
AU  - Benjamin Feller
AU  - Hideto Takahashi
TI  - SorCS1 inhibits amyloid-β binding to neurexin and rescues amyloid-β–induced synaptic pathology
AID  - 10.26508/lsa.202201681
DP  - 2023 Apr 01
TA  - Life Science Alliance
PG  - e202201681
VI  - 6
IP  - 4
4099  - https://www.life-science-alliance.org/content/6/4/e202201681.short
4100  - https://www.life-science-alliance.org/content/6/4/e202201681.full
SO  - Life Sci. Alliance2023 Apr 01; 6
AB  - 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 with NRX1β on the axon surface, and axonal expression of SorCS1b rescues AβO-induced impairment of NRX-mediated presynaptic organization and presynaptic vesicle recycling and AβO-induced structural defects in excitatory synapses. Thus, our data suggest a role for SorCS1 in the rescue of AβO-induced NRX dysfunction and synaptic pathology, providing the basis for a novel potential therapeutic strategy for Alzheimer’s disease.