CoChat
Sign Up
Cited by 92Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroscience and Neuropharmacology Research

Subtle behavioral changes and increased prefrontal-hippocampal network synchronicity in APPNL−G−F mice before prominent plaque deposition

Open access
Latif-Hernandez, Amira, Shah, Disha, Craessaerts, Kathleen, Saido, Takaomi, Saito, Takashi, De Strooper, Bart, Van der Linden, Annemie, D’Hooge, Rudi·2019·Behavioural Brain Research
DOI 10.1016/j.bbr.2017.11.017
Open this paper in CoChat — free accountOpen PDF

Abstract

Amyloid-β (Aβ) peptides occur in the brains of patients with Alzheimer's disease (AD), but their role in functional impairment is still debated. High levels of APP and APP fragments in mice that overexpress APP might confound their use in preclinical research. We examined the occurrence of behavioral, cognitive and neuroimaging changes in APP NL-G-F knock-in mice that display Aβ42 amyloidosis in the absence of APP overexpression. Female APP NL-G-F mice (carrying Swedish, Iberian and Arctic APP mutations) were compared to APP NL mice (APP Swedish) at 3, 7 and 10 months. Mice were subjected to a test battery that referred to clinical AD symptoms, comprising cage activity, open field, elevated plus maze, social preference and novelty test, and spatial learning, reversal learning and spatial reference memory performance. Our assessment confirmed that behavior at these early ages was largely unaffected in these mice in accordance with previous reports, with some subtle behavioral changes, mainly in social and anxiety-related test performance. Resting-state functional MRI (rsfMRI) assessed connectivity between hippocampal and prefrontal regions with an established role in flexibility, learning and memory. Increased prefrontal-hippocampal network synchronicity was found in 3-month-old APP NL-G-F mice. These functional changes occurred before prominent amyloid plaque deposition.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/j.bbr.2017.11.017

Cites

7 of 7 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • There was no overall genotype difference in circadian activity level when only comparing AppNL-G-F and AppNL-F genotypes.

    “Consistent with an earlier study, we did not observe an overall genotype differences in circadian activity level when only comparing the AppNL-G-F and AppNL-F genotypes39.”

    From Integrated analysis of behavioral, epigenetic, and gut microbiome analyses in AppNL-G-F, AppNL-F, and wild type mice (2021) · cites this paper as [39]

    Section 3.2 (page unavailable) reports significantly higher 23-hour activity in APP NL-G-F mice than APP NL mice at 3 and 10 months, contrary to the claimed absence of an overall genotype difference. It found no difference at 6 months. Our copy labels the comparison group APP NL, not AppNL-F. (LLM, conf=0.90)

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

  • The general behavioral phenotypes of App-KI mice described in many published studies are minimal, with the exception of robust alterations in emotional domains.

    “However, the general behavioral phenotypes of App-KI mice described in many published studies are minimal [9], with the exception of robust alterations in emotional domains [14, 21, 22].”

    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 [21]

    The Discussion reports subtle cognitive changes in APP NL-G-F mice, and the Discussion and §3.2 report reduced anxiety-related behavior, particularly in the elevated plus maze. This supports the pattern in the studied mice, but the paper does not establish that behavioral phenotypes are minimal across many published App-KI studies or that robust changes extend across emotional domains generally. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Findings on Morris water maze deficits in AppNL-G-F/NL-G-F mice are inconsistent: two groups reported no obvious deficits up to 12 months of age, whereas another reported robust deficits at 6 months of age.

    “for example, in the MWM task, two groups have reported that AppNL-G-F/NL-G-F mice develop no obvious deficits in spatial learning and memory up to 12 months of age [21, 23], whereas another reported robust learning and memory deficits in AppNL-G-F/NL-G-F mice at 6 months of age [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 [21]

    Section 3.4 (Spatial learning and memory; page unavailable) reports similar Morris water maze performance at 6–7 and 10–11 months, supporting the no-obvious-deficit part of the claim. The paper did not test mice at 12 months, and Section 3.5 reports a marginal reversal-memory difference at 6–7 months. The robust deficits attributed to [12] are not attributed to this source. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • 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 [21]

    The Discussion describes a relatively mild behavioral phenotype in the APP NL-G-F knock-in mice and says other models showed more robust reversal-learning impairments. It does not establish a field-wide consensus about cognitive abilities across App-KI mice; it also cautions that the compared studies used older animals with more advanced pathology. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • Humanized App knockin (KI) and APP transgenic mouse models mimic certain aspects of AD pathogenesis, including progressive amyloidosis, gliosis, and neuroinflammation, as well as network hyperexcitability and cognitive impairment, albeit to different degrees of severity across models and paradigms.

    “Humanized App knockin (KI) and APP transgenic mouse models mimic certain aspects of AD pathogenesis, including progressive amyloidosis, gliosis, and neuroinflammation, as well as network hyperexcitability and cognitive impairment, albeit to different degrees of severity across models and paradigms.15-27”

    From Machine learning reveals prominent spontaneous behavioral changes and treatment efficacy in humanized and transgenic Alzheimer's disease models (2024) · cites this paper as [17]

    The Discussion reports amyloid plaque deposition and neuroinflammation in APP NL-G-F mice, and contrasts their mild behavioral phenotype with more severe impairments reported in some APP-overexpressing models. Section 3.6 reports increased prefrontal-network synchrony at 3 months, but the paper does not establish that this is network hyperexcitability; the passages also do not address gliosis. The broad list of features is therefore only partly supported by this source. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 3

  1. I. Grundke-Iqbal, K. Iqbal, Y.C. Tung, M. Quinlan, H.M. Wisniewski, L.I. Binder, Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology, Proc. Natl. Acad. Sci. U. S. A. 83 (1986) 4913-4917.
  2. C. Sturchler-Pierrat, D. Abramowski, M. Duke, K.H. Wiederhold, C. Mistl, S. Rothacher, et al., Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology, Proc. Natl. Acad. Sci. U. S. A. 94 (1997) 13287-13292.
  3. D.G. Woolley, A. Laeremans, I. Gantois, D. Mantini, B. Vermaercke, H.P. Op de Beeck, N. Wenderoth, L. Arckens, R. D'Hooge, Homologous involvement of striatum and prefrontal cortex in rodent and human water maze learning, Proc. Natl. Acad. Sci. U. S. A. 110 (2013) 3131-3136.

Cited by

Sorted by citations

Authors
Latif-Hernandez, A., Shah, D., Craessaerts, K., Saido, T., Saito, T., De Strooper, B., Van der Linden, A., & D’Hooge, R.
Affiliations
  • University of Antwerp (BE)
  • RIKEN Center for Brain Science (JP)
  • KU Leuven (BE)
Corresponding author
D’Hooge, Rudi
ORCID
Venue
Behavioural Brain Research
Publisher
Elsevier BV
Published
2019-05
Volume
364
Pages
431-441
ISSN
0166-4328 (ISSN-L)
DOI
10.1016/j.bbr.2017.11.017
OpenAlex
W2770390952
Cited by
92
References
7
Citations by year
2026: 8 · 2025: 13 · 2024: 13 · 2023: 4 · 2022: 15 · 2021: 14 · 2020: 6 · 2019: 12 · 2018: 6 · 2017: 1
FWCI
5.08
Type
journal article
Language
en
Open access
Licence
Locations
  • Behavioural Brain Research (publishedVersion)
  • PubMed (publishedVersion)
  • Lirias (submittedVersion, other-oa)
  • UCL Discovery (University College London) (submittedVersion)
  • VUBIR (Vrije Universiteit Brussel) (submittedVersion)
Funders
federal science fund FWO-Vlaanderen (G058714, G0D76114)
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 › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
Alzheimer's disease, resting-state fMRI, social behavior, anxiety-like behavior, spatial learning and memory, APP mutations
MeSH terms
Alzheimer Disease, Animals, Anxiety, Behavior, Animal, Brain, Cognition, Disease Models, Animal, Female, Hippocampus, Magnetic Resonance Imaging, Mice, Transgenic, Rest, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Mice, Gene Knock-In Techniques, Plaque, Amyloid, Cognitive Dysfunction, Spatial Memory

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review