Overview
- Sanford Burnham Prebys scientists showed that raising levels of the brain protein SORLA in genetically engineered mice lowered tau hyperphosphorylation, limited spread of abnormal tau, preserved synapses, and reduced brain atrophy.
- Mice engineered to lack the Sorl1 gene that makes SORLA experienced the opposite outcome, with worse tau pathology and greater neurodegeneration, strengthening the link between SORLA abundance and disease severity.
- Researchers used single-cell and spatial profiling to show SORLA affects synaptic protein production and glial gene programs and identified upregulation of a plexin-B family receptor as a druggable node.
- The team plans experiments grafting human neurons or glia into mouse brains and screening candidate existing drugs for repurposing, but no human efficacy or safety data exist yet.
- The work builds on earlier findings that SORLA limits amyloid-beta and positions SORLA as a broader regulator of Alzheimer’s hallmarks and a potential target for therapies that must still clear human validation.