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

Alzheimer's disease (AD) remains a formidable challenge, with therapies targeting amyloid beta (Aβ) proving ineffective. Synapse loss is a major contributor to cognitive decline, exacerbated by Aβ oligomers (AβOs) that bind to various synaptic membrane proteins, including neurexin. Neurexin, a synaptic organizer, plays a crucial role in maintaining synaptic integrity and function.

However, the protein sorting receptor SorCS1 has been found to counteract these detrimental effects, though its therapeutic potential in vivo is still unknown.

To investigate SorCS1's role, researchers utilized 5xFAD mice, a model known for overproducing AβOs. By combining these mice with forebrain-specific neuronal SorCS1 overexpression, they discovered that SorCS1 preserves working memory, synaptic integrity, and basal excitatory transmission. Importantly, this enhancement occurred without altering amyloid deposition, suggesting SorCS1's ability to mitigate AD's cognitive impairments independent of amyloid reduction.

SorCS1 achieves these effects by restoring synaptic levels of β-neurexin, a protein critical for synaptic function. Furthermore, SorCS1 reduces tau hyperphosphorylation, a hallmark of AD pathology, and directly binds a tau kinase called GSK3β. These findings reveal SorCS1 as a promising factor promoting cognitive resilience and synaptic connectivity in AD, offering a novel therapeutic approach that operates independently of amyloid reduction.