Neuronal maturation is altered during pre-pathological stages in the App NL-F mouse model of Alzheimer's disease

Background An increased understanding of neuronal development in the early stages of Alzheimer's disease (AD) could shed light on the pathogenesis of the disease. Our previous proteomics studies of the knock-in App NL-F AD mouse model showed changes in neuritogenesis and neurogenesis early in life. Objective We aimed to characterize neuronal maturation across different stages of the progression of AD. Methods To this end, we immunolabeled doublecortin and phosphorylated doublecortin in primary neurons, and brain sections from App NL-F mice of varying ages and postmortem AD brain. Results Increased doublecortin and decreased phosphorylated doublecortin levels were observed in several cortical regions of embryonic App NL-F mice. Moreover, increased number of doublecortin positive cells was observed in the hippocampus of 6- and 12-month-old App NL-F mice. Doublecortin decreased over time in primary neuronal cultures of App NL-F and wild-type mice in a similar way. Likewise, doublecortin in postmortem human brains did not differ between AD patients and controls. Conclusions We conclude that a marker of immature neurons is unchanged in AD patients and aged mice but is altered in the early lifespan of App NL-F mice, before the onset of symptoms and pathology. These results suggest that neuronal maturation may also be dysregulated in the early, but not later, stages of AD.