Early-onset Amyloid Deposition and Cognitive Deficits in Transgenic Mice Expressing a Double Mutant Form of Amyloid Precursor Protein 695*

By Azhar M. Chishti, Dun-Sheng Yang, C. Janus, A. Phinney, P. Horne, J. Pearson, R. Strome, Noah Zuker, J. Loukides, J. French and 12 more. Journal of Biological Chemistry, 2001

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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 β-peptide (Aβ) 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 Aβ 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 Aβ42 per g brain at age 6 months, with an excess of Aβ42 over Aβ40. High level production of the pathogenic Aβ42 form of Aβ 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 Aβ42 (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.

Subfields: Computational Theory and Mathematics, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/a5af53d9a88de7ccfeaad235c67f0924d86478a1

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Citations in the corpus

The Relationship between Aβ and Memory in the Tg2576 Mouse Model of Alzheimer's Disease (2002, result): “This observation is supported by studies in TgCRND8 mice showing a rapid rise in A at 10 weeks, probably indicative of the appearance of A insol, before the demonstration of spatial memory deficits at 11 weeks (Chishti et al., 2001).”
Using mice to model Alzheimer's dementia: an overview of the clinical disease and the preclinical behavioral changes in 10 mouse models (2014, background): “(Promoter: PrP, Symbol: Tg (PRNP-APPSweInd) 8Dwst, MGI ID: 3589475) TheTgCRND8 model, described by Chishti et al. (2001), exhibits early cognitive impairment that spans across multiple cognitive domains (Chishti et al., 2001).”
Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer's disease mouse models. (2010, positive): “Excitotoxicity has been linked to premature lethality in APP transgenic mice (Chishti et al., 2001; El Khoury et al., 2007; Leissring et al., 2003; Roberson et al., 2007).”
Folic Acid Deficiency and Homocysteine Impair DNA Repair in Hippocampal Neurons and Sensitize Them to Amyloid Toxicity in Experimental Models of Alzheimer's Disease (2002, methodology): “…Norman Haughey,1 Jaewon Lee,1 Michele Evans,2 and Mark P. Mattson1,3 Laboratories of 1Neurosciences and 2Cellular and Molecular Biology, National Institute on Aging Gerontology Research Center, Baltimore, Maryland 21224, and 3Department of Neuroscience, Johns Hopkins University School of Medicine,”
Expression of a noncoding RNA is elevated in Alzheimer's disease and drives rapid feed-forward regulation of β-secretase (2008, background): “APP transgenic mice have increased levels of Bace1 -AS Tg19959 mice, considered a mouse model of Alzheimer's disease, overexpress a doubly mutated human APP (APP-tg19959”
APP mouse models for Alzheimer's disease preclinical studies (2017, neutral): “Frequently used models include PDAPP (Games et al , 1995), Tg2576 (Hsiao et al , 1996), APP23 (Sturchler-Pierrat et al , 1997), J20 (Mucke et al , 2000), and TgCRND8 (Chishti et al , 2001).”