β‐Amyloid precursor protein is modified with O‐linked N‐acetylglucosamine

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Abstract
The β-amyloid precursor protein (APP) has been implicated in the etiology of Alzheimer's disease (Kang et al.: Nature 325:733–736, 1987; Selkoe: Science 248:1058–1060, 1990; Selkoe: In Cowan et al. (eds): “Annual Review of Neuroscience.” Palo Alto, CA: Annual Reviews, Inc., pp 489–519, 1994) and numerous studies have shown that b̃-amyloid is involved in amyloid plaque formation (Rumble et al.: N Engl J Med 320:1446–1452, 1989; Sisodia et al.: Science 248: 492–495, 1990). Evidence is presented that APP is modified with N-acetylglucosamine linked to cytoplasmic serine or threonine residues (O-GIcNAc). This is the first report of a plasma membrane protein modified with this carbohydrate. It has been postulated that this modification, which is ubiquitous in all organisms studied to date except bacteria (Haltiwanger et al.: Biochem Soc Trans 20:264–269, 1992; Dong et al.: J Biol Chem 268:16679–16687, 1993; Elliot et al.: J Neurosci 13:2424–2429, 1993; Kelly et al.: J Biol Chem 268:10416–10424, 1993), may function as an alternative to phosphorylation (Dong et al., 1993) and is involved in the multimerization of proteins (Haltiwanger et al., 1992; Dong et al., 1993). O-GlcNAc occurs at “PEST” sequences (Rogers et al.: Science 234:364–368, 1986) and it has been suggested that this modification within such a sequence leads to increased proteolytic stability of the molecule (Dong et al., 1993). The importance of proteolytic cleavage (Kang et al., 1987; Selkoe, 1990, 1994), and the possible involvement of phosphorylation (Gandy et al.: Proc Natl Acad Sci USA 85:6218–6221, 1988; Gillespie et al.: Biochem Biophys Res Commun 187: 1285–1290, 1992; Suzuki et al.: J Neurosci 48:755–761, 1992; Suzuki et al.: EMBO J 13:1114–1122, 1994) in the regulation of APP processing suggest that this novel modification may somehow be involved in the biochemistry of APP.