Cell Surface Receptor Mediated Control of Amyloid Precursor Protein Secretion: Involvement of Pleiotropic Signal Transduction Cascades

Abstract

Amyloid plaques associated with brain vasculature and parenchyma are the pathological hallmark of Alzheimer’s Disease (AD) (Joachim and Selkoe, 1992). The deposits contain a variety of proteins but are mainly composed of a peptide with 39 to 43 amino acids, the ß-amyloid peptide (ß/A4). ß/A4 is derived from the proteolytic processing of a larger protein, the amyloid precursor protein (APP). APP is a family of membrane associated glycoproteins that are constitutively synthesized by a variety of cells including neurons and glia (Estus et al., 1992; Shoji et al., 1992; Busciglio et al., 1993). Proteolytic cleavage at a single site in its ß/A4 region releases the majority of APP from cells and at the same time eliminates the production of ß/A4 (Weidemann et al., 1989; Anderson et al., 1992). Alternatively, APP is processed by a second pathway that leads to the formation of intact, amyloidogenic ß/A4 (Haass et al., 1991; Golde et al., 1992; Hung et al., 1992). Cells normally produce small amounts of ß/A4, but genetic mutations (Cai et al., 1993a; Haass et al., 1993) and trauma (Roberts et al., 1991) can enhance the expression of the peptide.