Xenografted Human IPSC-derived Neurons with the Familial Alzheimer's Disease APP Mutation Reveal Dysregulated Transcriptome Signatures Linked to Synaptic Function and Implicate LINGO2 As a Disease Signaling Mediator

Alzheimer's disease (AD) is the most common cause of dementia, and disease mechanisms are still not fully understood. Here, we explored pathological changes in human induced pluripotent stem cell (iPSC)-derived neurons carrying the familial AD APP mutation after cell injection into the mouse forebrain. APP mutant iPSCs and isogenic controls were differentiated into neurons revealing enhanced Aβ production, elevated phospho-tau, and impaired neurite outgrowth in APP neurons. Two months after transplantation, APP and control neural cells showed robust engraftment but at 12 months post-injection, APP grafts were smaller and demonstrated impaired neurite outgrowth compared to controls, while plaque and tangle pathology were not seen. Single-nucleus RNA-sequencing of micro-dissected grafts, performed 2 months after cell injection, identified significantly altered transcriptome signatures in APP iPSC-derived neurons pointing towards dysregulated synaptic function and axon guidance. Interestingly, APP neurons showed an increased expression of genes, many of which are also upregulated in postmortem neurons of AD patients including the transmembrane protein LINGO2. Downregulation of LINGO2 in cultured APP neurons rescued neurite outgrowth deficits and reversed key AD-associated transcriptional changes related but not limited to synaptic function, apoptosis and cellular senescence. These results provide important insights into transcriptional dysregulation in xenografted APP neurons linked to synaptic function, and they indicate that LINGO2 may represent a potential therapeutic target in AD.