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Background  Knock-in (KI) mouse models of Alzheimer’s disease (AD) that endogenously overproduce Aβ 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 Aβ 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 Aβ 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 Aβ40 and Aβ42 in their brains.    Conclusions  Aβ 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.    Electronic supplementary material  The online version of this article (10.1186/s12868-019-0496-6) contains supplementary material, which is available to authorized users.

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