Increased Insoluble Amyloid-β Induces Negligible Cognitive Deficits in Old AppNL/NL Knock-In Mice
Open accessAbstract
Commonly used Alzheimer's disease mouse models are based on the ectopic overexpression of the human amyloid precursor protein (APP) gene, together with a mutant presenilin gene. Surprisingly, humanized APP knock-in mouse models carrying a single APP Swedish mutation (AppNL), failed to develop amyloid plaque aggregation or cognitive deficits. Here we characterized the effect of this mutation in more advanced ages. We show that 24-month-old AppNL/NL mice, despite presenting an age dependent increase in insoluble amyloid-β oligomers in the prefrontal cortex, they do not develop amyloid plaque deposition, reactive gliosis, or cognitive deficits.
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AppNL 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 [13]
The Introduction (page unavailable) says the Swedish mutation increases Aβ production and that AppNL/NL mice lack plaques and reactive gliosis. The Results (page unavailable) find significantly higher insoluble Aβ40 and Aβ42 in older versus younger AppNL/NL mice, but soluble levels decrease with age. Thus, the paper supports the pathology claim and a qualified increase in both peptides, not an unqualified significant increase in their levels. (LLM, conf=0.83)
Experimental — accuracy not yet measuredResearchers 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 [13]
AppNL 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 [13]
AppNL/NL mice overproduce human Aβ40 and Aβ42 in their brains.
“despite overproducing human Aβ40 and Aβ42 in their brains [10, 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 [13]
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 [13]
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- Authors
- Salas, I. H., Callaerts-Vegh, Z., D’Hooge, R., Saido, T. C., Dotti, C. G., & De Strooper, B.
- Affiliations
- VIB-KU Leuven Center for Brain & Disease Research (BE)
- Laboratory of Biological Psychology, KU Leuven, Leuven, Belgium
- KU Leuven (BE)
- RIKEN (JP)
- Consejo Superior de Investigaciones Científicas (ES)
- VIB Center for Brain and Disease Research, Leuven, Belgium
- Corresponding author
- Dotti, Carlos G.
- Venue
- Journal of Alzheimer's Disease
- Publisher
- SAGE Publications
- Published
- 2018-10-30
- Volume
- 66
- Issue
- 2
- Pages
- 801-809
- ISSN
- 1387-2877 (ISSN-L)
- 1875-8908
- PMC
- PMC6218137
- OpenAlex
- W2894970185
- Cited by
- 12
- References
- 33
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 2 · 2023: 2 · 2021: 3 · 2020: 1 · 2019: 1
- FWCI
- 0.86
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Alzheimer s Disease (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Lirias (KU Leuven) (submittedVersion, cc-by-nc)
- UCL Discovery (University College London) (submittedVersion)
- VUBIR (Vrije Universiteit Brussel) (submittedVersion)
- Funders
- Alzheimer Society
- Fonds Wetenschappelijk Onderzoek
- KU Leuven
- Vlaamse regering
- Medical Research Council
- 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, amyloid-beta oligomers
- MeSH terms
- Aging, Alzheimer Disease, Animals, Conditioning, Psychological, Cues, Disease Models, Animal, Exploratory Behavior, Fear, Gene Expression Regulation, Male, Mice, Inbred C57BL, Mice, Transgenic, Mutation, Social Behavior, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Prefrontal Cortex, Maze Learning, Mice, Cognitive Dysfunction
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