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

Abstract

DEPOSITS of β-amyloid are one of the main pathological charac-teristics of Alzheimer's disease. The β-amyloid peptide constituent (relative molecular mass 4,200) of the deposits is derived from the β-amyloid precursor protein (β-APP) which is expressed in several different isoforms^1–6. The two most prevalent β-APP isoforms are distinguished by either the presence (β-APP751) or absence (β-APP695) of a Kunitz serine protease inhibitor domain. Changes in the abundance of different β-APP messenger RNAs in brains of Alzheimer's disease victims have been widely reported^7–12. Although these results have been controversial, most evidence favours an increase in the mRNAs encoding protease inhibitor-containing isoforms of β-APP and it is proposed that this change contributes to β -amyloid formation^9–12. We have now produced an imbalance in the normal neuronal ratio of β-APP isoforms by preparing transgenic mice expressing additional β-APP751 under the control of a neural-specific promoter. The cortical and hip-pocampal brain regions of the transgenic mice display extracellular β -amyloid immunoreactive deposits varying in size (<5–50μm) and abundance. These results suggest that one mechanism of β-amyloid formation may involve a disruption of the normal ratio of neuronal β-APP isoform expression and support a direct relationship between increased expression of Kunitz inhibitor-bearing β-APP isoforms and β-amyloid deposition.