The role of post-translational modification in beta-amyloid precursor protein processing.
The beta-amyloid precursor protein (APP) plays a pivotal role in the early stages of neurodegeneration associated with Alzheimer's disease. An alteration in the processing pattern of the protein results in an increase in the generation of the 40-42-amino-acid beta-amyloid (A beta) peptide, which coalesces to form insoluble, extracellular amyloid deposits. A greater understanding of the factors that influence APP processing may assist in the design of effective therapeutic agents to halt progression of Alzheimer's disease. APP is a sialoglycoprotein with two potential N-linked glycosylation sites, one of which may contain a complex oligosaccharide chain. An alteration in the glycosylation state of APP by the generation of oligomannosyl oligosaccharides results in a decrease in the secretion of the neuroprotective, soluble form of the protein and a parallel increase in the deposition of the cellular protein within the perinuclear region of the cell. Conversely, the attachment of additional terminal sialic acid residues on to the oligosaccharide chain results in an increase in secretion of soluble APP (sAPP alpha). One factor that has been widely reported to alter APP processing is the activation of protein kinase C (PKC). This process has been characterized using synaptosomal preparations, which suggests that the PKC action is occurring at the level of the plasma membrane. Furthermore, when cells are transfected with the sialyltransferase enzyme, there is a direct relationship between the sialylation potential of APP and the fold stimulation of sAPP alpha, after PKC activation. These results suggest that the post-translational modification of APP by glycosylation is a key event in determining the processing of the protein.
Georgopoulou
N
N
Department of Pharmacology and Neuroscience, University of Dundee, Ninewells Hospital Medical School, Dundee DD1 9SY, U.K.
McLaughlin
M
M
McFarlane
I
I
Breen
K C
KC
D000544:Alzheimer Disease / Q000209:etiology* / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D002240:Carbohydrate Sequence; D006031:Glycosylation; D006801:Humans; D008969:Molecular Sequence Data; D009410:Nerve Degeneration / Q000378:metabolism; D009844:Oligosaccharides / Q000737:chemistry; D011493:Protein Kinase C / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D015290:Second Messenger Systems
D016564:Amyloid beta-Protein Precursor; D009844:Oligosaccharides; D011493:Protein Kinase C