Chimeric models of neurodegenerative diseases: from disease mechanisms to regenerative therapies

Abstract Human-rodent chimeric CNS models provide a unique platform for investigating human-specific aspects of neurodegeneration within the physiological environment of the living CNS. These models are generated by transplanting human pluripotent stem cell-derived neurons, astrocytes, microglia, oligodendrocytes, or neural or glial progenitor cells into the CNS of permissive host animals. Following transplantation, human cells mature, functionally integrate within host tissue, and retain key species-specific molecular and cellular features. Here, we review recent advances in the use of chimeric models to investigate disease mechanisms in Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, and demyelinating disorders. We highlight the unique insights these models have provided into human-specific cellular vulnerabilities, genotype-dependent phenotypes, glial responses, and neuroimmune interactions in vivo . We also discuss emerging translational applications, including cell replacement therapies, engineered glial delivery platforms, and remyelination strategies, some of which have progressed toward clinical translation. Finally, we outline the current limitations and future directions for developing next-generation multi-lineage humanized models with enhanced disease fidelity and translational potential.