APP ^NL-F knock-in Alzheimer’s Disease model mice reveal etiological convergence of aging and amyloidosis

Abstract Alzheimer’s disease (AD) is the leading cause of dementia worldwide, with a steadily increasing prevalence. Despite the advent of some plaque-degrading therapies, early intervention strategies are still suboptimal, largely due to an incomplete understanding of how early pathological events of amyloid-β (Aβ) plaque deposition entail or accompany the neuroinflammatory processes that ensue. The APP NL-F mouse line is a second-generation endogenous-promoter knock-in AD model that represents a valuable tool to dissect disease mechanisms and evaluate therapeutic strategies. However, the early prodromal stage remains poorly characterized. Here we performed in-depth analyses in both homozygous (APP NL-F/NL-F ) and heterozygous (APP NL-F/WT ) mice at 3, 6, 9 and 12 months of age. Among a battery of behavioural tests, the first phenotype was observed at 9 months with defects in spatial memory. Using hypersensitive MSD-ELISA technology assays we quantified distinct Aβ species and found that Aβ42 oligomers, protofibrils, and fibrillar aggregates were detectable as early as 6 months of age in homozygous APP NL-F/NL-F mice. By 9 months, their Aβ42 levels increased markedly and overt Aβ plaques were detected, histologically associated with recruited glial cells. Targeted RT-qPCR analysis of neuroinflammation-related genes in the cortex also identified 9 months as a molecular tipping point in these ‘middle aged’ APP NL-F mice. To characterize the etiological signal transduction at the cellular level, we isolated microglia, the brain resident immune cells, whose contribution to AD pathogenesis is now well established. Sequencing around 5,000 individual cells from both 12-month-old APP NL-F/NL-F and APP WT/WT CD11b+ myeloid cells revealed that the buildup of amyloidosis was associated with an accelerated shift of microglia from a homeostatic toward a senescent-like state. Together, these findings highlight the 6-12 month period of the APP NL-F/NL-F model as a powerful system to study the interdependence between microglial senescence and amyloidosis in driving AD progression.