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PreprintCited by 43Alzheimer's disease research and treatmentsNeuroscience and Neuropharmacology ResearchDementia and Cognitive Impairment Research

Insoluble Aβ overexpression in an App knock-in mouse model alters microstructure and gamma oscillations in the prefrontal cortex, and social and anxiety-related behaviours

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Pervolaraki, Eleftheria, Hall, Stephen P, Foresteire, Denise, Saito, Takashi, Saido, Takaomi C, Whittington, Miles A, Lever, Colin, Dachtler, James·2018·Disease Models & Mechanisms
DOI 10.1101/494443PMC PMC6765200

Preprint — published as 10.1242/dmm.040550

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Abstract

We studied two new App knock-in mice models of Alzheimer’s disease ( App NL-F and App NL-G-F ), which generate elevated levels of Aβ 40 and Aβ 42 without the confounds associated with APP overexpression. This enabled us to assess changes in anxiety-related and social behaviours, and neural alterations potentially underlying such changes, driven specifically by Aβ accumulation. App NL-G-F knock-in mice exhibited subtle deficits in tasks assessing social memory, but not in social motivation tasks. In anxiety-assessing tasks, App NL-G-F knock-in mice exhibited: 1) increased thigmotaxis in the Open Field (OF), yet; 2) reduced closed-arm, and increased open-arm, time in the Elevated Plus Maze (EPM). Their ostensibly-anxiogenic OF profile, yet ostensibly-anxiolytic EPM profile, could hint at altered cortical mechanisms affecting decision-making (e.g. ‘disinhibition’), rather than simple core deficits in emotional motivation. Consistent with this possibility, alterations in microstructure, glutamatergic-dependent gamma oscillations, and glutamatergic gene expression were all observed in the prefrontal cortex, but not the amygdala, of App NL-G-F knock-in mice. Thus, insoluble Aβ overexpression drives prefrontal cortical alterations, potentially underlying changes in social and anxiety-related behavioural tasks. Highlights: App NL-G-F KI mice displayed differing anxiety behaviours in two tests of anxiety. Prefrontal gamma was no longer NMDA-receptor dependent in App NL-G-F KI mice. Prefrontal expression of Grin2b was reduced in App NL-G-F KI mice. DTI found structural alterations in the hippocampus and prefrontal cortex in App NL-G-F KI mice.

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Cited by

Sorted by citations

Authors
Pervolaraki, E., Hall, S. P., Foresteire, D., Saito, T., Saido, T. C., Whittington, M. A., Lever, C., & Dachtler, J.
Affiliations
  • University of Leeds (GB)
  • University of York (GB)
  • Durham University (GB)
  • RIKEN Center for Brain Science (JP)
Corresponding author
Dachtler, James
ORCID
Venue
Disease Models & Mechanisms
Publisher
openRxiv
Published
2018-12-16
Volume
12
Issue
9
ISSN
1754-8403 (ISSN-L)
DOI
10.1101/494443
PMC
PMC6765200
OpenAlex
W2969868199
Cited by
43
References
0
Citations by year
2026: 2 · 2025: 6 · 2024: 4 · 2023: 2 · 2022: 10 · 2021: 10 · 2020: 6 · 2019: 3
FWCI
4.92
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Disease Models & Mechanisms (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
  • Durham Research Online (Durham University) (acceptedVersion, other-oa)
  • Durham Research Online (Durham University) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • HighWire Press Open Archive (submittedVersion)
Funders
  • Wellcome Trust
  • Alzheimer's Society (AS-JF-15-008)
  • Directorate for Biological Sciences
  • Biotechnology and Biological Sciences Research Council (BB/M008975/1)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
amyloid-beta, APP knock-in mice, Alzheimer's disease, Swedish mutation, prefrontal cortex, gamma oscillations, cortical microstructure, anxiety-like behavior, elevated plus maze, thigmotaxis, disinhibition, decision-making
MeSH terms
Animals, Anxiety, Behavior, Animal, Disease Models, Animal, Female, Gene Expression Regulation, Male, Mice, Inbred C57BL, Mice, Transgenic, Social Behavior, Solubility, Task Performance and Analysis, Receptors, N-Methyl-D-Aspartate, N-Methylaspartate, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Anisotropy, Prefrontal Cortex, Gene Knock-In Techniques, Gamma Rhythm

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