Formation of β-amyloid protein deposits in brains of transgenic mice

• Published in: Nature (London) 1991-07, Vol.352 (6332), p.239-241
• Main Authors: QUON, D, WANG, Y, CATALANO, R, SCARDINA, J, MURAKAMI, K, CORDELL, B
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - genetics; Amyloid beta-Peptides - analysis; Amyloid beta-Peptides - biosynthesis; Amyloid beta-Peptides - genetics; Amyloid beta-Protein Precursor; Analytical, structural and metabolic biochemistry; Animals; Base Sequence; beta -amyloid; beta -amyloid protein; Biological and medical sciences; Blotting, Western; Brain - metabolism; Female; Fundamental and applied biological sciences. Psychology; Genotype; Humans; Immunoenzyme Techniques; Male; Mice; Mice, Transgenic; Miscellaneous; Molecular Sequence Data; Oligonucleotide Probes; Protein Precursors - analysis; Protein Precursors - biosynthesis; Protein Precursors - genetics; Proteins; transgenic mice
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/352239a0

Deposits of beta-amyloid are one of the main pathological characteristics of Alzheimer's disease. The beta-amyloid peptide constituent (relative molecular mass 4,200) of the deposits is derived from the beta-amyloid precursor protein (beta-APP) which is expressed in several different isoforms. The two most prevalent beta-APP isoforms are distinguished by either the presence (beta-APP751) or absence (beta-APP695) of a Kunitz serine protease inhibitor domain. Changes in the abundance of different beta-APP messenger RNAs in brains of Alzheimer's disease victims have been widely reported. Although these results have been controversial, most evidence favours an increase in the mRNAs encoding protease inhibitor-containing isoforms of beta-APP and it is proposed that this change contributes to beta-amyloid formation. We have now produced an imbalance in the normal neuronal ratio of beta-APP isoforms by preparing transgenic mice expressing additional beta-APP751 under the control of a neural-specific promoter. The cortical and hippocampal brain regions of the transgenic mice display extracellular beta-amyloid immunoreactive deposits varying in size (less than 5-50 microns) and abundance. These results suggest that one mechanism of beta-amyloid formation may involve a disruption of the normal ratio of neuronal beta-APP isoform expression and support a direct relationship between increased expression of Kunitz inhibitor-bearing beta-APP isoforms and beta-amyloid deposition.