Formation of beta-amyloid protein deposits in brains of transgenic mice.
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.
Quon
D
D
California Biotechnology Inc., Mountain View 94043.
Wang
Y
Y
Catalano
R
R
Scardina
J M
JM
Murakami
K
K
Cordell
B
B
D000544:Alzheimer Disease / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics*; D016564:Amyloid beta-Protein Precursor; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism*; D005260:Female; D005838:Genotype; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D015345:Oligonucleotide Probes; D011498:Protein Precursors / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics*
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D015345:Oligonucleotide Probes; D011498:Protein Precursors