A Humanized Knock-in Mouse Model of the PSEN1 V97L Mutation from a Major Chinese Alzheimer's Disease Pedigree Reveals...

Mutations in the presenilin-1 (PSEN1) gene cause familial Alzheimer's disease (FAD). The PSEN1 V97L mutation is prevalent in Chinese FAD families. Previous studies using a transgenic model that overexpresses PSEN1 V97L have substantially contributed to understanding FAD pathogenesis. However, these models have limitations, including random genetic integration of the transgene, supra-physiological protein expression levels, and retention of endogenous mouse PSEN1 genes. The genetic engineering of novel mouse models carrying human mutant PSEN1 using knock-in methods addresses many of these issues. Here, we generated a humanized PSEN1 V97L knock-in (hV97L) mouse model. At 4 months of age, hV97L mice exhibited early neuroinflammation characterized by microglial activation and M1-like polarization, without Aβ pathology. By 8 months, cognitive deficits, dendritic loss, and myelin damage emerged, still in the absence of amyloid pathology. Our findings demonstrate that the PSEN1 V97L mutation triggers neuroinflammation before cognitive onset, providing a clinically relevant model for early therapeutic targeting.