The role of post-translational modification in ϐ-amyloid precursor protein processing

Abstract

The ϐ-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 ϐ-amyloid (Aϐ) 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 (sAPPα). 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 sAPPα, 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.

Age-Dependent Neurodegeneration and Alzheimer-Amyloid Plaque Formation in TransgenicDrosophila

“…An interference of post-translational modifications with APP processing has been reported previously (Tomita et al, 1998;Galbete et al, 2000;Georgopoulou et al, 2001). The processing of human APP in transgenic flies lacking BACE leads to the generation of a slightly larger peptide, ␦-A␤, by cleavage aminoterminally to the usual ␤-cleavage site.…”

SorLA Complement-type Repeat Domains Protect the Amyloid Precursor Protein against Processing

“…Glycosylation, particularly sialylation, of APP has been proposed to influence the processing pathway of APP by determining its passage from the Golgi to the cell membrane (50,71,72). Additionally, a study by Tomita et al (73) concluded that APP is only cleaved after maturation by O-glycosylation, which occurs during the transport of APP through the Golgi complex.…”

CK2 Phosphorylates the Angiotensin-Converting Enzyme and Regulates Its Retention in the Endothelial Cell Plasma Membrane

“…23 CK2 can also phosphorylate E-cadherin and the disruption of the adherens junction is associated with a decreased phosphorylation of E-cadherin by CK2. 24 Interestingly, the only other type I ectoprotein that is reported to be regulated by CK2 is the CD10/neutral endopeptidase 24,11,25 which also plays a key role in the degradation of bradykinin in endothelial cells. 26 Although PKC has been reported to associate with testis ACE, 27 we were unable to detect any such association in endothelial cells.…”

“…8 The cleavage/secretion of testis ACE is reported to be a regulated process that can be stimulated by phorbol 12-myristate 13-acetate (PMA), 9 a property that ACE shares with other ectoproteins such as tumor necrosis factor-␣ 10 and ␤-amyloid precursor protein. 11 Apart from the fact that somatic ACE is less efficiently cleaved than testis ACE, 7,12 and that ACE shedding is sensitive to metalloprotease inhibitors, 13,14 little or nothing is known about the mechanisms controlling the cleavage/secretion of somatic ACE from endothelial cells.…”