Regulation of Amyloid Precursor Protein Cleavage

Mills, Julia; Reiner, Peter B.

doi:10.1046/j.1471-4159.1999.0720443.x

Cited by 214 publications

(194 citation statements)

References 244 publications

(315 reference statements)

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“…This proteolytic cleavage constitutes the non-amyloidogenic pathway because it occurs within the b-amyloid (Ab) sequence, thereby preventing the formation of amyloidogenic fragments. The Ab peptide is formed and secreted as a physiological product of cell metabolism as a product of 'b-' and 'g-secretase' that cleave at the N and C termini of Ab respectively (reviewed by Mills and Reiner 6 and Racchi and Govoni 7 ). Both pathways are physiologically present in virtually all cell types and result in constitutive secretion of sAPPa and Ab.…”

Section: Introductionmentioning

confidence: 99%

Role of protein kinase Cα in the regulated secretion of the amyloid precursor protein

et al. 2003

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Protein kinase C (PKC) has a key role in the signal transduction machinery involved in the regulation of amyloid precursor protein (APP) metabolism. Direct and indirect receptor-mediated activation of PKC has been shown to increase the release of soluble APP (sAPPa) and reduce the secretion of b-amyloid peptides. Experimental evidence suggests that specific isoforms of PKC, such as PKCa and PKCe, are involved in the regulation of APP metabolism. In this study, we characterized the role of PKCa in the regulated secretion of APP using wild-type SH-SY5Y neuroblastoma cells and cells transfected with a plasmid expressing PKCa antisense cDNA. Cells expressing antisense PKCa secrete less sAPPa in response to phorbol esters. In contrast, carbachol increases the secretion of sAPPa to similar levels in wild-type cells and in cells transfected with antisense PKCa by acting on APP metabolism through an indirect pathway partially involving the activation of PKC. These results suggest that the direct PKC-dependent activation of the APP secretory pathway is compromised by reduced PKCa expression and a specific role of this isoform in these mechanisms. On the other hand, indirect pathways that are also partially dependent on the mitogen-activated protein kinase signal transduction mechanism remain unaffected and constitute a redundant, compensatory mechanism within the APP secretory pathway.

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Section: Introductionmentioning

confidence: 99%

Role of protein kinase Cα in the regulated secretion of the amyloid precursor protein

et al. 2003

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“…Alzheimer's disease is a progressive neurodegenerative disorder characterized by the occurrence of senile plaques and neurofibrillary tangles throughout the brain cortex. The major component of the senile plaques is the amyloid β-peptide (Aβ), of M r $ 4 kDa, which is derived from the larger type I integral membrane APP, through sequential proteolytic cleavage by β-and γ-secretases [33,34]. APP can also be processed through a non-amyloidogenic pathway in which α-secretase cleaves the protein within the Aβ sequence, thereby precluding the formation of Aβ.…”

Section: Introductionmentioning

confidence: 99%

Amyloid precursor protein, although partially detergent-insoluble in mouse cerebral cortex, behaves as an atypical lipid raft protein

Parkin

Turner

Hooper

1999

Biochemical Journal

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Lipid rafts are regions of the plasma membrane that are enriched in cholesterol, glycosphingolipids and acylated proteins, and which have been proposed as sites for the proteolytic processing of the Alzheimer's amyloid precursor protein (APP). Lipid rafts can be isolated on the basis of their insolubility in Triton X-100 at 4 mC, with the resulting low-density, detergent-insoluble glycolipid-enriched fraction (DIG) being isolated by flotation through a sucrose density gradient. The detergent-insolubility of APP in mouse cerebral cortex relative to a variety of DIG marker proteins (alkaline phosphatase, flotillin, F3 protein and prion protein) and non-DIG proteins (alkaline phosphodiesterase I, aminopeptidase A and clathrin) has been examined. Alkaline phosphatase, flotillin, F3 protein and the prion protein were present exclusively in the DIG region of the sucrose gradient over a range of protein\detergent ratios used to solubilize the membranes and displayed a characteristic enrichment in the lowdensity fraction as the protein\detergent ratio was decreased. In

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“…AD is characterized pathologically by the deposition of extracellular amyloid, containing the ␤-amyloid protein (A␤) (Glenner and Wong, 1984;Masters et al, 1985), which is derived from a 110 -130-kDa ␤-amyloid protein precursor (APP) (Kang et al, 1987). Cleavage of APP by ␤-and ␥-secretases results in the production of a peptide with 39 -43 amino acid residues (for review, see Mills and Reiner, 1999). Although A␤1-40 is the predominant form of A␤, the production of A␤1-42 may be linked more closely to disease pathogenesis (Suzuki et al, 1994;Mehta et al, 1998).…”

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confidence: 99%

Substrate‐Bound β‐Amyloid Peptides Inhibit Cell Adhesion and Neurite Outgrowth in Primary Neuronal Cultures

Postuma

Nunan

et al. 2000

Journal of Neurochemistry

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Accumulation of the ␤-amyloid protein (A␤) in the brain is an important step in the pathogenesis of Alzheimer's disease. However, the mechanism of A␤ toxicity remains unclear. A␤ can bind to the extracellular matrix, a structure that regulates adhesive events such as neurite outgrowth and synaptogenesis. The binding of A␤ to the extracellular matrix suggests that A␤ may disrupt cell-substrate interactions. Therefore, the effect of substrate-bound A␤ on the growth of isolated chick sympathetic and mouse cortical neurons was examined. A␤1-40 and A␤1-42 had dose-dependent effects on cell morphology. When tissue culture plates were coated with 0.1-10 ng/well A␤, neurite outgrowth increased. Higher amounts of A␤ peptides (Ն3 g/well) inhibited outgrowth. The inhibitory effect was related to aggregation of the peptide, as preincubation of A␤1-40 for 24 h at 37°C (a process known to increase amyloid fibril formation) was necessary for inhibition of neurite outgrowth. A␤29 -42, but not A␤1-28, also inhibited neurite outgrowth at high concentrations, demonstrating that the inhibitory domain is located within the hydrophobic C-terminal region. A␤1-40, A␤1-42, and A␤29 -42 also inhibited cell-substrate adhesion, indicating that the effect on neurite outgrowth may have been due to inhibition of cell adhesion. The results suggest that accumulation of A␤ may disrupt celladhesion mechanisms in vivo.

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Regulation of Amyloid Precursor Protein Cleavage

Cited by 214 publications

References 244 publications

Role of protein kinase Cα in the regulated secretion of the amyloid precursor protein

Role of protein kinase Cα in the regulated secretion of the amyloid precursor protein

Amyloid precursor protein, although partially detergent-insoluble in mouse cerebral cortex, behaves as an atypical lipid raft protein

Substrate‐Bound β‐Amyloid Peptides Inhibit Cell Adhesion and Neurite Outgrowth in Primary Neuronal Cultures

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