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Modulation of APP Processing by Neurotransmission

1995; Springer Nature; Linguagem: Inglês

10.1007/978-1-4757-9145-7_16

0099-6246

Roger M. Nitsch, Barbara E. Slack, Steven Farber, Meihua Deng, Paul R. Borghesani, Richard J. Wurtman, John H. Growdon,

Glycosylation and Glycoproteins Research

Brain amyloid deposits are invariant neuropathological hallmarks of Alzheimer’s disease (AD) and Down’s syndrome, and are sometimes also found in lesser amounts in brains of neuropsychologically normal, aged human subjects. AD-type brain amyloid consists of aggregated Aß peptides which are 39–43 amino acid residues in length. Aß is derived, by proteolytic processing, from a larger amyloid ß-protein precursor (APP), which is a transmembrane glycoprotein that contains a single membrane spanning domain, a large N-terminal ectodomain and a short cytoplasmic C-terminal tail. The Aß domain is located within the ectodomain and extends with its hydrophobic C-terminal region 11-15 residues into the membrane. APP exists in various forms generated by alternative splicing of mRNA derived from a single gene on chromosome 21 (for review, see Kosik, 1992). APP is highly conserved and expressed at high levels in brain and, at lower levels, in many peripheral tissues. The biological function of APP is unclear but accumulating evidence suggests roles in cell adhesion (Schubert et al., 1989), in neurite outgrowth (Milward et al., 1992), as well as excitoprotective functions via the regulation of intracellular calcium concentrations (Mattson et al., 1993). Mature APP is rapidly degraded by various alternative proteolytic processing pathways. Proteolytic derivatives are secreted into the extracellular space and are found at high concentrations in human cerebrospinal fluid. Secreted APP derivatives include the large N-terminal ectodomain, termed APPs (Esch et al., 1990; Sisodia et al., 1990) and ~4KDa Aß-peptides (Haass et al., 1992; Shoji et al., 1992) that potentially can aggregate into amyloid. In addition to the secretory processing pathways, full-length APP can be internalized from the cell surface and targeted to the endosomal-lysosomal system (Haass et al., 1992), where multiple cleavage products are generated. Some of these contain the intact ßA4 domain and thus are also potentially amyloidogenic (Golde et al., 1992; Estus et al., 1992). Aß is neurotoxic in some experimental systems (Yankner et al., 1990) and may induce apoptosis (Loo et al., 1993). Thus, APP processing pathways yielding either Aß or APPs are likely to have distinct cellular consequences: processing events that generate Aß may be toxic and are potentially amyloidogenic, whereas APP processing to yield APPs generate trophic and precludes APP’s role as an amyloidogenic molecule. It thus becomes important to understand the cellular mechanisms involved in the regulation of APP processing pathways.