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Cited by 90Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

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

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Sakakibara, Yasufumi, Sekiya, Michiko, Saito, Takashi, Saido, Takaomi C., Iijima, Koichi M.·2018·BMC Neuroscience
DOI 10.1186/s12868-018-0446-8PMC PMC6064053
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Abstract

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.

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References 76 · Cited by 90

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Authors
Sakakibara, Y., Sekiya, M., Saito, T., Saido, T. C., & Iijima, K. M.
Affiliations
  • National Center for Geriatrics and Gerontology (JP)
  • Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology (JP)
  • RIKEN Center for Brain Science (JP)
  • Nagoya City University (JP)
Corresponding author
  • Sakakibara, Yasufumi
  • Iijima, Koichi M.
ORCID
Venue
BMC Neuroscience
Publisher
Springer Science and Business Media LLC
Published
2018-07-28
Volume
19
Issue
1
Pages
46-46
ISSN
1471-2202 (ISSN-L)
DOI
10.1186/s12868-018-0446-8
PMC
PMC6064053
OpenAlex
W2883703220
Cited by
90
References
76
Citations by year
2026: 14 · 2025: 16 · 2024: 15 · 2023: 7 · 2022: 9 · 2021: 10 · 2020: 11 · 2019: 8
FWCI
4.99
Type
journal article
Language
en
Open access
Licence
Locations
  • BMC Neuroscience (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Center for Geriatrics and Gerontology (28-26)
  • Japan Society for the Promotion of Science (18K15381, 16K08637)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
Alzheimer's disease, APP knock-in mice, familial Alzheimer's disease mutations, Swedish mutation, Arctic mutation, anxiolytic-like behavior, anxiogenic-like behavior, contextual fear conditioning, spatial learning, preclinical Alzheimer's disease
MeSH terms
Alzheimer Disease, Amyloidosis, Animals, Behavior, Animal, Cognition Disorders, Disease Models, Animal, Emotions, Mice, Transgenic, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Gene Knock-In Techniques, Cognitive Dysfunction

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