ABSTRACT
In 1984, Glenner and Wong first isolated and purified the subunit protein of the meningovascular amyloid filaments in AD and determined its amino-terminal sequence (Glenner and Wong, 1984). They named this novel protein the amyloid β-peptide (Aβ). Shortly thereafter, compacted amyloid plaque cores were partially purified from AD cerebral cortex and shown to consist of essentially the same Aβ peptide (Masters et al., 1985; Gorevic et al., 1986; Roher et al., 1986; Selkoe et al., 1986). Based on the partial amino acid sequence, cDNAs encoding part or all of the Aβ precursor were cloned (Goldgaber et al., 1987; Kang et al., 1987; Robakis et al., 1987; Tanzi et al., 1987). The deduced amino acid sequence obtained from a full-length cDNA predicted a 695 amino acid type I transmembrane protein containing a 17 residue signal peptide, a single membrane-spanning region and a short cytoplasmic tail. The Aβ sequence was predicted to begin 28 residues amino-terminal to the transmembrane domain and extend 11-15 residues into that domain (Figure 1). Various major isoforms of APP result from alternative splicing of at least three exons in the APP gene. The most
widely and abundantly expressed of these is the 751 amino acid form containing exon 7, which encodes a 56 amino acid region with structural and functional properties of a serine protease inhibitor of the Kunitz-type (KPI) (Kitaguchi et al., 1988; Ponte et al., 1988; Tanzi et al., 1988). The isoform of APP which is selectively expressed in neurons lacks exon 7 and contains 695 amino acids. In contrast, astrocytes and microglia selectively express isoforms lacking exon 15, which encodes a small region prior to the transmembrane domain (called L-APP isoforms) (Konig et al., 1992).
