Cognitive and emotional alterations in App knock-in mouse models of Aβ amyloidosis

Abstract

Abstract Background Alzheimer’s disease (AD), the most common cause of dementia, is characterized by the progressive deposition of amyloid-β (Aβ) peptides and neurofibrillary tangles. Mouse models of Aβ amyloidosis generated by knock-in (KI) of a humanized Aβ sequence provide distinct advantages over traditional transgenic models that rely on overexpression of amyloid precursor protein (APP). In App-KI mice, three familial AD-associated mutations were introduced into the endogenous mouse App locus to recapitulate Aβ pathology observed in AD: the Swedish (NL) mutation, which elevates total Aβ production; the Beyreuther/Iberian (F) mutation, which increases the Aβ42/Aβ40 ratio; and the Arctic (G) mutation, which promotes Aβ aggregation. App NL-G-F mice harbor all three mutations and develop progressive Aβ amyloidosis and neuroinflammatory response in broader brain areas, whereas App NL mice carrying only the Swedish mutation exhibit no overt AD-related pathological changes. To identify behavioral alterations associated with Aβ pathology, we assessed emotional and cognitive domains of App NL-G-F and App NL mice at different time points, using the elevated plus maze, contextual fear conditioning, and Barnes maze tasks. Results Assessments of emotional domains revealed that, in comparison with wild-type (WT) C57BL/6J mice, App NL-G-F/NL-G-F mice exhibited anxiolytic-like behavior that was detectable from 6 months of age. By contrast, App NL/NL mice exhibited anxiogenic-like behavior from 15 months of age. In the contextual fear conditioning task, both App NL/NL and App NL-G-F/NL-G-F mice exhibited intact learning and memory up to 15–18 months of age, whereas App NL-G-F/NL-G-F mice exhibited hyper-reactivity to painful stimuli. In the Barnes maze task, App NL-G-F/NL-G-F mice exhibited a subtle decline in spatial learning ability at 8 months of age, but retained normal memory functions. Conclusion App NL/NL and App NL-G-F/NL-G-F mice exhibit behavioral changes associated with non-cognitive, emotional domains before the onset of definitive cognitive deficits. Our observations consistently indicate that App NL-G-F/NL-G-F mice represent a model for preclinical AD. These mice are useful for the study of AD prevention rather than treatment after neurodegeneration.

Keywords

• Alzheimer’s disease
• Amyloid precursor protein
• Knock-in mouse model
• Emotional behavior
• Spatial learning