“Secretase,” Alzheimer amyloid protein precursor secreting enzyme is not sequence-specific

Maruyama, Kei; Kametani, Fuyuki; Usami, Mihoko; Yamao‐Harigaya, Wakako; Tanaka, Kunihito

doi:10.1016/0006-291x(91)91767-7

Cited by 101 publications

(53 citation statements)

References 16 publications

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“…Membrane association and co-localization of enzyme and substrate (APP) appears to be required for the activity of α-secretase [36][37][38]. However, neither the precise cellular localization nor the identity of the enzyme have been elucidated [36,39].…”

Section: Discussionmentioning

confidence: 99%

Secretory processing of amyloid precursor protein is inhibited by increase in cellular cholesterol content

Racchi

Baetta

Salvietti

et al. 1997

Biochemical Journal

150

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Plasma-membrane composition plays a crucial role in most of the cellular functions that depend on membrane processes. In virtually all cell types the proteolytic processing of Alzheimer amyloid precursor protein (APP) to generate soluble APP (sAPP) is believed to occur at the plasma membrane or in its immediate proximity. Alteration of this metabolic pathway has been linked to the pathogenesis of Alzheimer's disease. We analysed the effect of membrane cholesterol enrichment on APP metabolism. Incubation of COS cells with increasing concentrations of nonesterified cholesterol carried by rabbit β-very low-density lipoprotein caused a dose-dependent inhibition of sAPP release : 70 % inhibition with 10 µg\ml non-esterified cholesterol. A less pronounced inhibitory effect was observed on treatment with

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Section: Discussionmentioning

confidence: 99%

Secretory processing of amyloid precursor protein is inhibited by increase in cellular cholesterol content

Racchi

Baetta

Salvietti

et al. 1997

Biochemical Journal

150

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“…Membrane association and colocalization of enzyme and substrate (APP) are critical for the activity of ␣ -secretase (58,59). ␣ -Secretase cleavage requires that APP be inserted into a membrane, and it cleaves APP at a fixed distance from the membrane rather than at a specific amino acid sequence (60).…”

Section: Cholesterol and App Processingmentioning

confidence: 99%

Membrane dynamics, cholesterol homeostasis, and Alzheimer's disease

Chauhan

2003

Journal of Lipid Research

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Alzheimer's disease (AD) is characterized by the deposition of ␤ -amyloid (A ␤ ) plaques derived from the amyloidogenic processing; of a transmembrane protein called ␤ -amyloid precursor protein (APP). In addition to the known genetic/sporadic factors that promote the formation of A ␤ , the composition and structural dynamics of the membrane are also thought to play a significant role in the amyloidogenic processing of APP that promotes seeding of A ␤ . This minireview reinforces the roles played by membrane dynamics, membrane microdomains, and cholesterol homeostasis in relation to amyloidogenesis, and reviews current strategies of lowering cholesterol in treating AD. -N STRUCTURE OF CELL MEMBRANEBiological membranes play a critical role in carrying out almost all physiological functions of the cell. The molecular organization of the cell membrane forms an infrastructural basis for all specialized function(s) carried out by the cell membrane. Many model membranes of varying molecular organization have been hypothesized and proposed to justify membrane functions (1-4). Among these, a dynamic fluid mosaic model (5) that evolved after several hypothetical modifications (6-8) has become a widely accepted model applicable to most biological membranes. Fluid mosaic model of cell membraneAccording to this classic model, membrane is composed of a bulk of phospholipid organized as a bilayer, with globular integral proteins embedded within the phospholipid texture. Phospholipids are arranged with their ionic and polar head groups in direct contact with the aqueous phase at the exterior and interior surfaces of the bilayer ( Fig. 1 , black gradient-filled circles), thereby maximizing hydrophilic interactions at the aqueous surfaces, while the nonpolar saturated fatty acid chains interdigitate within the interior of the membrane bilayer, forming a matrix (5). Voids and spaces between these chain aggregates are filled with lipids, of which cholesterol constitutes a major component (9, 10). The lipid matrix of the model membrane exists in three different phases, i.e., gel, liquid-ordered, and liquid-disordered states, in order of increasing fluidity (11). In the gel state, lipids are semifrozen; in the liquid-ordered state, lipids are viscous; and in the liquid-disordered state, lipids exist as fluids. This liquid-disordered fluid phase is essential for protein functions (12). The liquid-disordered fluid phase can be transformed to the liquid-ordered or gel state by tight packing of phospholipids and hydrocarbon chains with cholesterol intercalations in order of increasing rigidity (9). Thus, the amount of cholesterol present in the membrane determines the fluid/rigid state of the membrane.Integral membrane proteins [membrane anchor proteins, i.e., glycophosphatidylinositol (GPI), Src -family proteins, receptor ligands, signaling molecules, transmembrane proteins] are embedded within the phospholipid bilayer with their ionic and highly polar groups protruding to the exterior surface, and nonpolar groups largely bur...

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“…This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. amino acid sequence specificity of ␣-secretase at the cleavage site in APP is low (3,8,16,17), the question is raised how other integral membrane proteins in the default secretory pathway escape this enzymatic activity. Specific targeting of APP by undefined sorting signals to a "secretase compartment" (3) or specific binding of the secretase to a region of APP outside the ␤A4-amyloid peptide sequence, lending specificity to the cleavage process, are two possibilities that remain to be further explored.…”

Section: Amyloid Precursor Protein (App)mentioning

confidence: 99%

Exchanging the Extracellular Domain of Amyloid Precursor Protein for Horseradish Peroxidase Does Not Interfere with α-Secretase Cleavage of the β-Amyloid Region, but Randomizes Secretion in Madin-Darby Canine Kidney Cells

Strooper

Craessaerts

Leuven

et al. 1995

Journal of Biological Chemistry

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Secretory processing and polarized sorting of horseradish peroxidase fused to the amyloid precursor protein transmembrane domain were compared with those of wild-type amyloid precursor protein in COS and polarized Madin-Darby canine kidney (MDCK) cells. The cellular and secreted forms of the chimeric protein were enzymatically active in colorimetric and cytochemical assays after reconstitution with hemin and Ca 2؉ . The peroxidase enzyme was secreted by a proteolytic process, similar to the parent amyloid precursor protein. In polarized MDCK cells, amyloid precursor protein was secreted exclusively in the basolateral compartment, while the peroxidase chimeric protein was secreted in both compartments. The basolateral sorting determinant for secretion must therefore be located in the extracellular domain of amyloid precursor protein. On the other hand, cell surface-associated peroxidase chimeric protein was similar to cell surface-associated wild-type amyloid precursor protein, mainly expressed at the basolateral side. The basolateral cell-surface expression, in contrast to the basolateral secretion, is therefore controlled by determinants in the cytoplasmic domain. Methylamine inhibited and bafilomycin slightly increased the basolateral secretion of both proteins, but both drugs strongly increased apical secretion. The default secretory pathway of COS cells and the basolateral (but not the apical) secretory pathway of MDCK cells are therefore comparably sensitive to methylamine and not to bafilomycin. Amyloid precursor protein (APP)1 is the precursor of the ␤A4-amyloid peptide, a 4-kDa protein that precipitates in the amyloid plaques in the brains of Alzheimer's patients. The metabolism of the protein is complex and occurs along several possible pathways, all involving proteolytic cleavages of the precursor protein (reviewed in Ref. 1). The normal secretory processing of APP takes place in a late compartment of the default secretory pathway (2-4) by an ␣-secretase cleavage in the ␤A4-amyloid peptide sequence itself (5-8). This cleavage step yields the soluble extracellular domain of APP (APP s ) and precludes further amyloid formation. APP that escapes from this activity is transported to the cell surface and endocytosed (9). Alternative proteolytic cleavages, possibly in the endosomes, release the ␤A4-amyloid peptide and/or the p3-peptide (1). These fragments are secreted with APP s by all cell types studied until now. Interestingly, amyloid lesions in the brains of Alzheimer's patients are always associated with polarized cell types, e.g. neurons and endothelial cells. This raises the question whether APP and its proteolytic products are transported and secreted in a polarized way, i.e. in neurons to the axons or dendrites and in epithelial cells to the apical or basolateral side. It was recently demonstrated that in primary cultures of hippocampal neurons, APP is transported first to the axons and later to the dendrites (10, 11). In polarized epithelial Madin-Darby canine kidney (MDCK) cells, APP and its vari...

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“Secretase,” Alzheimer amyloid protein precursor secreting enzyme is not sequence-specific

Cited by 101 publications

References 16 publications

Secretory processing of amyloid precursor protein is inhibited by increase in cellular cholesterol content

Secretory processing of amyloid precursor protein is inhibited by increase in cellular cholesterol content

Membrane dynamics, cholesterol homeostasis, and Alzheimer's disease

Exchanging the Extracellular Domain of Amyloid Precursor Protein for Horseradish Peroxidase Does Not Interfere with α-Secretase Cleavage of the β-Amyloid Region, but Randomizes Secretion in Madin-Darby Canine Kidney Cells

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