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bioRxiv · 10.1101/2022.07.26.501499

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

Lee, A.·Yi, N.·Khaled, H.·Feller, B.·Chofflet, N.·Takahashi, H.
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Abstract

Amyloid-{beta} oligomers (A{beta}Os), toxic peptide aggregates found in Alzheimers disease (AD), cause synapse pathology. A{beta}Os 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 A{beta} pathology was previously unstudied. Here, we show competitive interaction of SorCS1 and A{beta}Os with {beta}-NRXs and rescue effects of SorCS1 on A{beta}O-induced synaptic pathology. Like A{beta}Os, SorCS1 binds to NRX1{beta} through the histidine-rich-domain (HRD) of NRX1{beta}, and SorCS1 and A{beta}Os compete for NRX1{beta} binding. In cultured hippocampal neurons, SorCS1 colocalizes with NRX1{beta} on the axon surface, and axonal expression of SorCS1 rescues A{beta}O-induced impairment of NRX-mediated presynaptic organization and presynaptic vesicle recycling as well as A{beta}O-induced structural defects in excitatory synapses. Thus, we reveal a role of SorCS1 in the rescue of A{beta}O-induced NRX dysfunction and synaptic pathology, providing the basis for a novel potential therapeutic strategy for AD.

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Lee, A., Yi, N., Khaled, H., Feller, B., Chofflet, N., Takahashi, H.. 2022-07-28. SorCS1 inhibits amyloid-β binding to neurexin and rescues amyloid-β-induced synaptic pathology. https://doi.org/10.1101/2022.07.26.501499

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