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Cognitive and emotional alterations in App knock-in mouse models of A? amyloidosis.

ABSTRACT: BACKGROUND:Alzheimer's disease (AD), the most common cause of dementia, is characterized by the progressive deposition of amyloid-? (A?) peptides and neurofibrillary tangles. Mouse models of A? amyloidosis generated by knock-in (KI) of a humanized A? 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 A? pathology observed in AD: the Swedish (NL) mutation, which elevates total A? production; the Beyreuther/Iberian (F) mutation, which increases the A?42/A?40 ratio; and the Arctic (G) mutation, which promotes A? aggregation. AppNL-G-F mice harbor all three mutations and develop progressive A? amyloidosis and neuroinflammatory response in broader brain areas, whereas AppNL mice carrying only the Swedish mutation exhibit no overt AD-related pathological changes. To identify behavioral alterations associated with A? pathology, we assessed emotional and cognitive domains of AppNL-G-F and AppNL 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, AppNL-G-F/NL-G-F mice exhibited anxiolytic-like behavior that was detectable from 6 months of age. By contrast, AppNL/NL mice exhibited anxiogenic-like behavior from 15 months of age. In the contextual fear conditioning task, both AppNL/NL and AppNL-G-F/NL-G-F mice exhibited intact learning and memory up to 15-18 months of age, whereas AppNL-G-F/NL-G-F mice exhibited hyper-reactivity to painful stimuli. In the Barnes maze task, AppNL-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:AppNL/NL and AppNL-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 AppNL-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.

SUBMITTER: Sakakibara Y

PROVIDER: S-EPMC6064053 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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

Sakakibara Yasufumi Y Sekiya Michiko M Saito Takashi T Saido Takaomi C TC Iijima Koichi M KM

BMC neuroscience 20180728 1

<h4>Background</h4>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 locu ...[more]

PMID: 30055565

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Project description:BACKGROUND:Knock-in (KI) mouse models of Alzheimer's disease (AD) that endogenously overproduce A? 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 A? plaque formation and reactive gliosis in these mice. RESULTS:In 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 A? 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 A?40 and A?42 in their brains. CONCLUSIONS:A? 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.

Dataset Information

Cognitive and emotional alterations in App knock-in mouse models of A? amyloidosis.

Publications

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

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