Amyloid-β plaque formation and reactive gliosis are required for induction of cognitive deficits in App knock-in mouse models of Alzheimer's disease

Background: Knock-in (KI) mouse models of Alzheimer's disease (AD) that endogenously overproduce A beta without non-physiological overexpression of amyloid precursor protein (APP) provide important insights into the pathogenic mechanisms of AD. Previously, we reported that App(NL-G-F) mice, which harbor three familial AD mutations (Swedish, Beyreuther/Iberian, and Arctic) exhibited emotional alterations before the onset of definitive cognitive deficits. To determine whether these mice exhibit deficits in learning and memory at more advanced ages, we compared the Morris water maze performance of App(NL-G-F) and App(NL) mice, which harbor only the Swedish mutation, with that of wild-type (WT) C57BL/6J mice at the age of 24 months. To correlate cognitive deficits and neuroinflammation, we also examined A beta plaque formation and reactive gliosis in these mice. Results: In the Morris water maze, a spatial task, 24-month-old App(NL-G-F/NL-G-F) mice exhibited significantly poorer spatial learning than WT mice during the hidden training sessions, but similarly to WT mice during the visible training sessions. Not surprisingly, App(NL-G-F/NL-G-F) mice also exhibited spatial memory deficits both 1 and 7 days after the last training session. By contrast, 24-month-old App(NL/NL) mice had intact spatial learning and memory relative to WT mice. Immunohistochemical analyses revealed that 24-month-old App(NL-G-F/NL-G-F) mice developed massive A beta plaques and reactive gliosis (microgliosis and astrocytosis) throughout the brain, including the cortex and hippocampus. By contrast, we observed no detectable brain pathology in App(NL/NL) mice despite overproduction of human A beta 40 and A beta 42 in their brains. Conclusions: A beta plaque formation, followed by sustained neuroinflammation, is necessary for the induction of definitive cognitive deficits in App-KI mouse models of AD. Our data also indicate that introduction of the Swedish mutation alone in endogenous APP is not sufficient to produce either AD-related brain pathology or cognitive deficits in mice.