APOER2 splicing repertoire in Alzheimer's disease

Alternative splicing enhances genetic diversity by producing various RNA isoforms from a single gene. The gene LRP8 which encodes apolipoprotein E receptor 2, undergoes extensive alternative splicing in the brain. APOER2 is a type I transmembrane receptor that interacts with extracellular ligands including Reelin and APOE, a risk factor associated with Alzheimer's disease. Interestingly, alternative splicing of APOER2 has been shown to be altered in AD, yet the complete repertoire of APOER2 isoforms in both normal and AD affected brains remained largely unexplored. Our study offers insight into the diverse isoforms of APOER2 in the human brain and their splicing modifications in the context of AD. We discovered a range of combinatorial APOER2 alternative splicing events, leading to a diverse set of isoforms in the human brain. Our analysis revealed both region and disease specific APOER2 isoforms, indicating that APOER2 splicing is not only spatially regulated but also undergoes alterations in AD. Moreover, we observed that some of the APOER2 isoforms in AD brains show changes in cell surface expression, receptor processing and synapse numbers. These findings suggest that combinatorial splicing of APOER2 is a critical determinant of its protein function and undergoes significant alterations in AD.