Early-onset Amyloid Deposition and Cognitive Deficits in Transgenic Mice Expressing a Double Mutant Form of Amyloid Precursor Protein 695
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We have created early-onset transgenic (Tg) models by exploiting the synergistic effects of familial Alzheimer's disease mutations on amyloid beta-peptide (Abeta) biogenesis. TgCRND8 mice encode a double mutant form of amyloid precursor protein 695 (KM670/671NL+V717F) under the control of the PrP gene promoter. Thioflavine S-positive Abeta amyloid deposits are present at 3 months, with dense-cored plaques and neuritic pathology evident from 5 months of age. TgCRND8 mice exhibit 3,200-4,600 pmol of Abeta42 per g brain at age 6 months, with an excess of Abeta42 over Abeta40. High level production of the pathogenic Abeta42 form of Abeta peptide was associated with an early impairment in TgCRND8 mice in acquisition and learning reversal in the reference memory version of the Morris water maze, present by 3 months of age. Notably, learning impairment in young mice was offset by immunization against Abeta42 (Janus, C., Pearson, J., McLaurin, J., Mathews, P. M., Jiang, Y., Schmidt, S. D., Chishti, M. A., Horne, P., Heslin, D., French, J., Mount, H. T. J., Nixon, R. A., Mercken, M., Bergeron, C., Fraser, P. E., St. George-Hyslop, P., and Westaway, D. (2000) Nature 408, 979-982). Amyloid deposition in TgCRND8 mice was enhanced by the expression of presenilin 1 transgenes including familial Alzheimer's disease mutations; for mice also expressing a M146L+L286V presenilin 1 transgene, amyloid deposits were apparent by 1 month of age. The Tg mice described here suggest a potential to investigate aspects of Alzheimer's disease pathogenesis, prophylaxis, and therapy within short time frames.
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In TgCRND8 mice, significantly reduced numbers of PV-positive interneurons in the CA1/2 layer were detected at 1 month of age, preceding extracellular plaque deposition.
“In TgCRND8 mice, a model expressing human mutant APP with the Swedish and Indiana mutations and an early onset of plaque deposition at 3 months of age [39], significantly reduced numbers of PV-positive interneurons in the CA1/2 layer were detected at only 1 month of age, a time point preceding extracellular plaque deposition [130].”
From Neuron Loss in Alzheimer’s Disease: Translation in Transgenic Mouse Models (2020) · cites this paper as [39]
The discrepancy in cognitive profiles between BRI2-Aβ and APP transgenic mice cannot be easily attributed to mouse genetic background, since genetic background is comparable between BRI2-Aβ and CRND8 models.
“This discrepancy in cognitive profiles between BRI2-Aβ and APP transgenic mice, for example APP CRND8 model tested intensively in our laboratory, cannot be easily attributed to the mouse genetic background, which is known to modulate behavior [35-37], since genetic background is comparable between BRI2-Aβ and CRND8 models [7,9].”
From Normal cognition in transgenic BRI2-Aβ mice (2013) · cites this paper as [9]
The chosen experimental paradigms were successfully used in the lab to demonstrate impairment in APP CRND8 mice.
“The chosen experimental paradigms were successfully used in our lab to demonstrate impairment in APP CRND8 mice, and focused on spatial learning and reference memory evaluated in WM test [9,10,13] and conditioned taste aversion, a form of Pavlovian associative learning, [34], in addition to the context and tone conditioned fear memory paradigm [25]”
From Normal cognition in transgenic BRI2-Aβ mice (2013) · cites this paper as [9]
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- Authors
- 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., & Westaway, D.
- Affiliations
- University Health Network (CA)
- McLaughlin Research Institute (US)
- Corresponding author
- Westaway, David
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2001-06
- Volume
- 276
- Issue
- 24
- Pages
- 21562-21570
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2153747061
- Cited by
- 955
- References
- 74
- Citations by year
- 2026: 15 · 2025: 29 · 2024: 25 · 2023: 33 · 2022: 26 · 2021: 31 · 2020: 39 · 2019: 32 · 2018: 45 · 2017: 47 · 2016: 47 · 2015: 42 · 2014: 50 · 2013: 56 · 2012: 58
- FWCI
- 15.42
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- INFM-OAR (INFN Catania) (submittedVersion, other-oa)
- 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, familial Alzheimer's disease mutations, amyloid-beta, amyloid-beta 42, amyloid deposition, transgenic mice, TgCRND8 mice, presenilin 1, learning disabilities, reference memory, amyloid plaques, cognitive impairment
- MeSH terms
- Aging, Amyloid, Amyloidosis, Animals, Brain, Cognition Disorders, Crosses, Genetic, Female, Humans, Male, Mice, Inbred C3H, Mice, Inbred C57BL, Mice, Transgenic, Promoter Regions, Genetic, Restriction Mapping, Mutagenesis, Site-Directed, Amyloid beta-Protein Precursor, Maze Learning, Amino Acid Substitution, Mice
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 ›
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