ß-Amyloid Precursor Protein — Role in Cognitive Brain Function?

Abstract

Alzheimer’s disease (AD) is characterized by loss of higher brain functions and appearance of specific pathological lesions such as neurofibrillary tangles, ß-amyloid plaques and neuronal degeneration. As ß-amyloid generation and accumulation occur very early in the disease process the fate and role of its precursor proteins (ß-APPs) is important for understanding AD pathogenesis. The primary structure of ß-APP resembles glycosylated cell surface proteins (Kang et al., 1987) and they can be proteolyzed in two different ways giving rise either to extracellular secreted C-terminal truncated molecules or to the ß-amyloid peptide (Haass and Selkoe, 1993). Different length isoforms of ß-APP are derived from alternative NA splicing (ß-APP₆₉₅, ß-APP₇₅₁, ß-APP₇₇₀) all of which may be N-and O-glycosylated (Weidemann et al., 1989). The ß-APP gene products are expressed in different tissues and show highest abundance in neurons in the brain (Shivers et al., 1988). Co-localization of B-APP with synaptophysin was found at synaptic sites (Schubert et al., 1991) and ß-APP levels, in particular ß-APP₆₉₅, increase transiently during synaptogenesis in rats (Loftier and Huber, 1992). The potential roles of ß-APPs in higher brain function were explored by intracerebroventricular injection of anti-ß-APP antibodies in rats followed by behavioural analysis(Huber et al., 1993) and by comparison of ß-APP levels in brains of rats with different “cognitive” capabilities.