SorCS1 promotes synaptic and cognitive resilience despite amyloid pathology in Alzheimer's disease model mice

Authors

Yi, N., Lee, A. K., Bourojeni, F. B., Wang, M., Inagaki, M., Takahashi, H.

Abstract

Alzheimer's disease (AD) lacks effective therapies despite extensive efforts targeting amyloid {beta} (A{beta}) and its precursor processing. Synapse loss is the strongest correlate of cognitive decline, driven partly by A{beta} oligomers (A{beta}Os), which bind multiple synaptic membrane proteins including the synaptic organizer neurexin and disrupt synaptic integrity and function. The protein sorting receptor SorCS1 blocks interactions between A{beta}Os and {beta}-isoforms of neurexins ({beta}-Nrxns), but its therapeutic relevance in vivo remains unclear. Using 5xFAD mice, which overproduce A{beta}Os, combined with forebrain specific neuronal SorCS1 overexpression, we show that SorCS1 preserves working memory, synaptic integrity, and basal excitatory transmission without altering amyloid deposition, in part by restoring synaptic {beta}-Nrxn expression. SorCS1 also reduces tau hyperphosphorylation in 5xFAD synaptosomes and binds the tau kinase GSK3{beta}. These results identify SorCS1 as an AD resilience promoting factor that maintains synaptic connectivity and attenuates tau pathology, revealing a therapeutic strategy that operates independently of amyloid reduction.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 28 Aug 2026.

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