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

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.

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.

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.