Abstract
BackgroundKnock-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 AppNL-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 AppNL-G-F and AppNL 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.ResultsIn the Morris water maze, a spatial task, 24-month-old AppNL-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, AppNL-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 AppNL/NL mice had intact spatial learning and memory relative to WT mice. Immunohistochemical analyses revealed that 24-month-old AppNL-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 AppNL/NL mice despite overproduction of human Aβ40 and Aβ42 in their brains.ConclusionsAβ 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.
Highlights
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
These results suggest that AppNL-G-F mice develop emotional alterations prior to the emergence of the definitive cognitive deficits
Our results demonstrate that Aβ deposits, followed by sustained neuroinflammation, is required for induction of definitive cognitive deficits in App-KI mouse models of AD
Summary
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. We reported that AppNL-G-F mice, which harbor three familial AD mutations (Swedish, Beyreuther/Iberian, and Arctic) exhibited emotional alterations before the onset of definitive cognitive deficits. Several transgenic mouse lines overexpressing amyloid precursor protein (APP) that recapitulate amyloid-β (Aβ) deposition and the accompanying behavioral deficits have been instrumental to AD research [3,4,5,6] These mice may exhibit phenotypes because they overproduce various APP fragments in addition to Aβ [7,8,9]. To overcome this problem, alternative mouse models have been generated via knock-in (KI) of a humanized Aβ sequences harboring familial AD mutations (Swedish (NL), Beyreuther/Iberian (F), and Arctic (G)) in order to model Aβ amyloidosis without non-physiological overexpression of APP [10]. None of these App-KI mice exhibit tau pathology or severe neuronal loss, suggesting that they are suitable models for preclinical AD [9]
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