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Cited by 213Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsNicotinic Acetylcholine Receptors Study

Accelerated Plaque Accumulation, Associative Learning Deficits, and Up-regulation of α7 Nicotinic Receptor Protein in Transgenic Mice Co-expressing Mutant Human Presenilin 1 and Amyloid Precursor Proteins

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Dineley, Kelly T., Xia, Xuefeng, Bui, Duy, Sweatt, J. David, Zheng, Hui·2002·Journal of Biological Chemistry
DOI 10.1074/jbc.m200164200
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Abstract

Familial Alzheimer's disease-associated mutations in presenilin 1 or 2 or amyloid precursor protein result in elevated beta-amyloid, beta-amyloid accumulation, and plaque formation in the brains of affected individuals. By crossing presenilin 1 transgenic mice carrying the A246E mutation with plaque-producing amyloid precursor protein K670N/M671L transgenic mice (Tg2576), we show that co-expression of both mutant transgenes results in acceleration of amyloid accumulation and associative learning deficits. At 5 months of age with no detectable plaque pathology, amyloid precursor protein transgenic animals are impaired in contextual fear learning following two pairings of conditioned and unconditioned stimuli but appear normal following a more robust five-pairing training. At 9 months of age when beta-amyloid deposition is evident, these mice are impaired following both two-pairing and five-pairing protocols. Mice carrying both transgenes are impaired in contextual fear conditioning at either age. All transgenic animal groups performed as well as controls in cued fear conditioning, indicating that the contextual fear learning deficits are hippocampus-specific. The associative learning impairments are coincident with elevated alpha 7 nicotinic acetylcholine receptor protein in the dentate gyrus. These findings provide two robust and rapid assays for beta-amyloid-associated effects that can be performed on young animals: impaired contextual fear learning and up-regulation of alpha 7 nicotinic receptors.

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  • Increasing Aβ by expressing FAD mutant PS1 together with FAD mutant APP failed to produce substantial enhancements of the behavioral deficits observed in mice overexpressing FAD mutant APP alone.

    “Our findings are also consistent with research showing that increasing Ab by expressing FAD mutant PS1 together with FAD mutant APP failed to produce substantial enhancements of the behavioral deficits observed in mice overexpressing FAD mutant APP alone (56)(57)(58).”

    From Amyloid precursor protein-induced axonopathies are independent of amyloid-β peptides (2008) · cites this paper as [56]

    The Discussion (page not provided) says the contextual fear-learning deficit was more pronounced in PS-1/APP mice, contrary to the claim that adding mutant PS-1 failed to substantially enhance the behavioral deficit. The reported comparison at five months also found that APP-only mice performed significantly better than PS-1/APP mice after more intensive training. (LLM, conf=0.88)

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  • Fear in Tg2576 mice is a common observation made in this genotype.

    “Fear in Tg2576 mice is a common observation made in this genotype (Dineley et al., 2002).”

    From Arbovirus infection increases the risk for the development of neurodegenerative disease pathology in the murine model (2024) · cites this paper as Dineley et al., 2002

    The Results (page unavailable) report that APP mice showed no anomalous anxiety-related behavior in the open-field test, contrary to the claim that fear is a common characteristic of this genotype. The paper’s fear-conditioning results concern learned responses to a cue and foot shock, not a general observation that these mice are fearful. (LLM, conf=0.84)

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  • Tg2576 mice exhibit elevated Aβ from 2 months old onward, plaques after 6 months old, and cognitive deficits beginning at 5 months old.

    “Tg2576 mice exhibit elevated Aβ from 2 months old onward, plaques after 6 months old, and cognitive deficits beginning at 5 months old [32,33,34].”

    From VEEV TC-83 Triggers Dysregulation of the Tryptophan–Kynurenine Pathway in the Central Nervous System That Correlates with Cognitive Impairment in Tg2576 Mice (2024) · cites this paper as [33]

    The Results (page not supplied) report that APP-only Tg2576 mice were plaque-free at 7 months but had occasional cortical plaques at 9 months. The paper also reports impaired contextual fear learning at 5 months, but only after the two-pairing protocol; five pairings rescued that impairment. Our copy does not establish that Aβ was elevated from 2 months onward. (LLM, conf=0.87)

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  1. Lambert, M. P., Barlow, A. K., Chromy, B. A., Edwards, C., Freed, R., Liosatos, M., Morgan, T. E., Rozovsky, I., Trommer, B., Viola, K. L., Wals, P., Zhang, C., Finch, C. E., Krafft, G. A., and Klein, W. L. (1998) Proc. Natl. Acad. Sci.
  2. Chishti, M. A., Yang, D. S., Janus, C., Phinney, A. L., Horne, P., Pearson, J., Strome, R., Zuker, N., Loukides, J., French, J., Turner, S., Lozza, G., Grilli, M., Kunicki, S., Morissette, C., Paquette, J., Gervais, F., Bergeron, C., Fraser, P. E., Carlson, G. A., George-Hyslop, P. S., and Westaway, D. (2001) J. Biol. Chem. 276, 21562-21570
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Authors
Dineley, K. T., Xia, X., Bui, D., Sweatt, J. D., & Zheng, H.
Affiliations
Baylor College of Medicine (US)
Corresponding author
  • Dineley, Kelly T.
  • Sweatt, J. David
ORCID
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2002-06
Volume
277
Issue
25
Pages
22768-22780
ISSN
0021-9258 (ISSN-L)
DOI
10.1074/jbc.m200164200
OpenAlex
W1999234381
Cited by
212
References
38
Citations by year
2026: 1 · 2025: 4 · 2024: 3 · 2023: 2 · 2022: 1 · 2021: 3 · 2020: 6 · 2019: 9 · 2018: 9 · 2017: 10 · 2016: 9 · 2015: 8 · 2014: 10 · 2013: 7 · 2012: 15
FWCI
7.19
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Alzheimer's Association
  • National Alliance for Research on Schizophrenia and Depression
  • National Institutes of Health
  • National Institute on Aging
  • National Institute of Mental Health
  • National Institute of Neurological Disorders and Stroke
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
Keywords
familial Alzheimer's disease, presenilin 1, amyloid precursor protein, Tg2576 mice, amyloid-beta deposition, amyloid plaques, contextual fear conditioning, alpha7 nicotinic acetylcholine receptor, dentate gyrus, hippocampus, transgenic mice
MeSH terms
Age Factors, Animals, Behavior, Animal, Fear, Hippocampus, Immunohistochemistry, Learning, Membrane Proteins, Mice, Transgenic, Mutation, Protein Binding, Receptors, Nicotinic, Shock, Time Factors, Immunoblotting, Up-Regulation, Amyloid beta-Protein Precursor, Transgenes, Mice, Presenilin-1, alpha7 Nicotinic Acetylcholine Receptor

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