Cognitive deficits in single App knock-in mouse models
Open accessAbstract
Transgenic mouse models of Alzheimer's disease (AD) with nonphysiologic overexpression of amyloid precursor protein (APP) exhibit various unnatural symptoms/dysfunctions. To overcome this issue, mice with single humanized App knock-in (KI) carrying Swedish (NL), Beyreuther/Iberian (F), and Arctic (G) mutations in different combinations were recently developed. The validity of these mouse models of AD from a behavioral viewpoint, however, has not been extensively evaluated. Thus, using an automated behavior monitoring system, we analyzed various behavioral domains, including executive function, and learning and memory. The App-KI mice carrying NL-G-F mutations showed clear deficits in spatial memory and flexible learning, enhanced compulsive behavior, and reduced attention performance. Mice carrying NL-F mutations exhibited modest abnormalities. The NL-G-F mice had a greater and more rapid accumulation of Aβ deposits and glial responses. These findings reveal that single pathologic App-KI is sufficient to produce deficits in broad cognitive domains and that App-KI mouse lines with different levels of pathophysiology are useful models of AD.
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Researchers have reached a consensus that the alterations in cognitive abilities of App-KI mice are very mild relative to the phenotypes of other overexpression models.
“Accordingly, researchers have reached a consensus that the alterations in cognitive abilities of App-KI mice are very mild relative to the phenotypes of other overexpression models [11, 13, 21].”
From Amyloid-β plaque formation and reactive gliosis are required for induction of cognitive deficits in App knock-in mouse models of Alzheimer’s disease (2019) · cites this paper as [11]
The Abstract (page unavailable) reports clear cognitive deficits in NL-G-F App-KI mice, although abnormalities in NL-F mice were modest. Section 4.1 (page unavailable) says the App-KI behavioral abnormalities largely overlap with those reported in transgenic AD models and describes severe reversal-learning deficits in NL-G-F mice. This runs counter to the blanket characterization of App-KI cognitive changes as very mild relative to overexpression models; the paper also does not report a researcher consensus on that comparison. (LLM, conf=0.83)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredAppNL mice produce significantly higher levels of Aβ40 and Aβ42 without overt AD-related brain pathology such as extracellular Aβ plaques or neuroinflammation.
“By contrast, AppNL mice that carry only the Swedish mutation produce significantly higher levels of Aβ40 and Aβ42 without overt AD-related brain pathology such as extracellular Aβ plaques or neuroinflammation [10, 11, 13].”
From Amyloid-β plaque formation and reactive gliosis are required for induction of cognitive deficits in App knock-in mouse models of Alzheimer’s disease (2019) · cites this paper as [11]
The Introduction (page unavailable) identifies AppNL mice as carrying only the Swedish mutation and says their Aβ deposition and neuroinflammatory response are negligible. Section 3.6 (page unavailable) likewise reports that Aβ accumulation was difficult to detect in AppNL mice even at 18 months. The paper does not establish the claimed significant increases in both Aβ40 and Aβ42 in these mice. (LLM, conf=0.87)
Experimental — accuracy not yet measuredAppNL mice harbor only the Swedish mutation.
“By contrast, AppNL mice that carry only the Swedish mutation produce significantly higher levels of Aβ40 and Aβ42 without overt AD-related brain pathology such as extracellular Aβ plaques or neuroinflammation [10, 11, 13].”
From Amyloid-β plaque formation and reactive gliosis are required for induction of cognitive deficits in App knock-in mouse models of Alzheimer’s disease (2019) · cites this paper as [11]
In AppNL-G-F mice, Aβ amyloidosis is aggressive, and neuroinflammation is observed in subcortical structures as well as cortical regions.
“In AppNL-G-F mice, which harbor all three mutations, Aβ amyloidosis is aggressive, and neuroinflammation is observed in subcortical structures as well as cortical regions [10–12].”
From Amyloid-β plaque formation and reactive gliosis are required for induction of cognitive deficits in App knock-in mouse models of Alzheimer’s disease (2019) · cites this paper as [11]
Recent studies reported negligible cognitive deficits and lack of Aβ plaque formation in AppNL/NL mice.
“These results are consistent with recent studies reporting negligible cognitive deficits and the lack of Aβ plaque formation in AppNL/NL mice (Fig. 6) [10, 11, 13, 14, 24].”
From Amyloid-β plaque formation and reactive gliosis are required for induction of cognitive deficits in App knock-in mouse models of Alzheimer’s disease (2019) · cites this paper as [11]
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- Authors
- Masuda, A., Kobayashi, Y., Kogo, N., Saito, T., Saido, T. C., & Itohara, S.
- Affiliations
- RIKEN Center for Brain Science (JP)
- Corresponding author
- Itohara, Shigeyoshi
- Venue
- Neurobiology of Learning and Memory
- Publisher
- Elsevier BV
- Published
- 2016-11
- Volume
- 135
- Pages
- 73-82
- ISSN
- 1074-7427 (ISSN-L)
- OpenAlex
- W2472186754
- Cited by
- 248
- References
- 37
- Citations by year
- 2026: 20 · 2025: 32 · 2024: 35 · 2023: 17 · 2022: 28 · 2021: 43 · 2020: 25 · 2019: 20 · 2018: 19 · 2017: 9
- FWCI
- 12.88
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Neurobiology of Learning and Memory (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Funding Program for World-Leading Innovative R&D on Science and Technology
- 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 › Neurological Disease Mechanisms and Treatments
- Keywords
- Alzheimer's disease, amyloid precursor protein, APP knock-in mice, humanized mice, Swedish mutation, Arctic mutation, cognitive impairment, spatial memory, flexible learning, compulsive behavior, attention, amyloid-beta deposition, glial response, executive function, automated behavior monitoring
- MeSH terms
- Alzheimer Disease, Animals, Behavior, Animal, Disease Models, Animal, Female, Learning, Male, Mice, Transgenic, Amyloid beta-Protein Precursor, Mice, Executive Function, Cognitive Dysfunction, Spatial Memory
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