ABSTRACT
The capacity of the central nervous system to retain the experiences of an individual is a critical biological function. The significance of this function is no better illustrated than by considering the clinical consequences of Alzheimer’s disease (AD), well-characterized for causing progressive and permanent disruption of memory in affected individuals (Selkoe, 1994). There are a wide array of neuropathological features of AD which include the development of neurofibrillary tangles (Goedert et al., 1991; Lee and Trojanowski, 1992), neuronal loss (Cotman and Su, 1996; Gomez-Isla et al., 1996) and disturbances in a number of neurotransmitter systems (Palmer, 1996). However, the histopathological hallmark of AD is the florid deposition of compact and diffuse senile plaques (Tagliavini et al., 1988; Yamaguchi et al., 1988; Wisniewski et al., 1989). Amyloid β peptide (Aβ), the primary proteinaceous component of these plaques, ranges from 39-43 amino acids in length (Glenner and Wong 1984; Masters et al., 1985). Aβ is derived from post-translational cleavage of the amyloid precursor protein (APP) (Goldgaber et al., 1987; Tanzi et al., 1987; Kang et al., 1987; Robakis et al.,
1987). Alternative splicing of APP mRNAs can give rise to eight Aβ containing APP isoforms, of which APP 695, 751, and 770 are the three principal species (Figure 1). APP 751 differs from APP 695 by the inclusion of a 56 amino acid domain referred to as the Kunitz protease inhibitor domain (KPI) due to its homology to the Kunitz serine protease inhibitor family (Kang et al., 1987; Kitaguchi et al., 1988; Ponte et al., 1988; Tanzi et al., 1988). APP 770 contains the KPI domain, as well as a 19 amino acid sequence with homology to the MRC OX-2 antigen (Kitaguchi et al., 1988; Weidemann et al., 1989). Whether these domains influence the processing of APP has not been established.
