Dataset Information

Neural oscillations during cognitive processes in an App knock-in mouse model of Alzheimer's disease pathology.

ABSTRACT: Multiple animal models have been created to gain insight into Alzheimer's disease (AD) pathology. Among the most commonly used models are transgenic mice overexpressing human amyloid precursor protein (APP) with mutations linked to familial AD, resulting in the formation of amyloid ? plaques, one of the pathological hallmarks observed in AD patients. However, recent evidence suggests that the overexpression of APP by itself can confound some of the reported observations. Therefore, we investigated in the present study the AppNL-G-Fmodel, an App knock-in (App-KI) mouse model that develops amyloidosis in the absence of APP-overexpression. Our findings at the behavioral, electrophysiological, and histopathological level confirmed an age-dependent increase in A?1-42 levels and plaque deposition in these mice in accordance with previous reports. This had apparently no consequences on cognitive performance in a visual discrimination (VD) task, which was largely unaffected in AppNL-G-F mice at the ages tested. Additionally, we investigated neurophysiological functioning of several brain areas by phase-amplitude coupling (PAC) analysis, a measure associated with adequate cognitive functioning, during the VD task (starting at 4.5 months) and the exploration of home environment (at 5 and 8 months of age). While we did not detect age-dependent changes in PAC during home environment exploration for both the wild-type and the AppNL-G-F mice, we did observe subtle changes in PAC in the wild-type mice that were not present in the AppNL-G-F mice.

SUBMITTER: Jacob S

PROVIDER: S-EPMC6841667 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Neural oscillations during cognitive processes in an App knock-in mouse model of Alzheimer's disease pathology.

Jacob Sofia S Davies Gethin G De Bock Marijke M Hermans Bart B Wintmolders Cindy C Bottelbergs Astrid A Borgers Marianne M Theunis Clara C Van Broeck Bianca B Manyakov Nikolay V NV Balschun Detlef D Drinkenburg Wilhelmus H I M WHIM

Scientific reports 20191108 1

Multiple animal models have been created to gain insight into Alzheimer's disease (AD) pathology. Among the most commonly used models are transgenic mice overexpressing human amyloid precursor protein (APP) with mutations linked to familial AD, resulting in the formation of amyloid β plaques, one of the pathological hallmarks observed in AD patients. However, recent evidence suggests that the overexpression of APP by itself can confound some of the reported observations. Therefore, we investigat ...[more]

PMID: 31705038

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Project description: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.

Dataset Information

Neural oscillations during cognitive processes in an App knock-in mouse model of Alzheimer's disease pathology.

Publications

Neural oscillations during cognitive processes in an App knock-in mouse model of Alzheimer's disease pathology.

Similar Datasets

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