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PubMed: 10656250

Title
Identification of a novel aspartic protease (Asp 2) as beta-secretase.
Journal
Molecular and cellular neurosciences
Volume
14
Issue
None
Pages
419-27
Date
1999-12-01
Authors
Hussain I | Christie G | Chapman C | Dingwall C | Gloger IS | Howlett DR | Meek TD | Murphy KE | Powell D | Ryan DM | Simmons DL | Smith TS | Southan CD | Tew DG | Walsh FS

Evidence 38893da6ce
JSON

Using the same anti-peptide sera we can detect expression of endogenous Asp 2 in SH-SY5Y cells stably expressing the 695 isoform of APP (SH-SY5Y APP-695) and in COS-7 cells expressing the 751 isoform of APP (COS-7 APP-751). The level of Asp 2 is increased upon transient transfection with the protein.

a(HBP:APP695) association p(HGNC:BACE1) View Subject | View Object

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
SH-SY5Y

a(HBP:APP751) association p(HGNC:BACE1) View Subject | View Object

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
COS-7 cell

p(HGNC:BACE1) association a(HBP:APP695) View Subject | View Object

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
SH-SY5Y

p(HGNC:BACE1) association a(HBP:APP751) View Subject | View Object

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
COS-7 cell

Evidence a00397d4ef
JSON

APP clearly localizes to the Golgi/endoplasmic reticulum region as revealed by distinctive juxtanuclear staining and a more generalized reticular staining throughout the cell (Figs. 6b and 6g). Asp 2 shows essentially the same subcellular distribution as revealed by simultaneous detection of myc-tagged Asp 2 and APP in COS-7 APP-751 cells (compare Figs. 6f and 6g), and merging of the confocal images for APP and Asp 2 indicates colocalization (Fig. 6h).

p(HGNC:APP, loc(GO:"endoplasmic reticulum")) association p(HGNC:BACE1, loc(GO:"endoplasmic reticulum")) View Subject | View Object

Appears in Networks:

p(HGNC:BACE1, loc(GO:"endoplasmic reticulum")) association p(HGNC:APP, loc(GO:"endoplasmic reticulum")) View Subject | View Object

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Evidence 216cbf24fe
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Transient transfection of SH-SY5Y APP-695 cells with Asp 2 (Fig. 2a) results in a significant increase in the secretion of sAPPb (Fig. 2b) consistent with Asp 2 being b-secretase. To demonstrate that this increase in sAPPb is linked to the proteolytic activity of Asp 2, we mutated each of the proposed catalytic aspartic residues at positions 25 and 215 (determined by comparison with the position of the known catalytic aspartyl residues in pepsin) to asparagine. Both mutants and the wild-type Asp 2 are expressed to similar levels (Fig. 2a).

p(HGNC:BACE1) increases sec(a(HBP:"sAPP-beta")) View Subject | View Object

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
SH-SY5Y

Evidence db3a8573ed
JSON

However, expression of either of the Asp 2 mutants does not produce the increase in the secretion of sAPPb (Fig. 2b) seen for wild-type Asp 2. In contrast to this clear effect on sAPPb, Asp 2 has no effect on the secretion of soluble APPa or on full-length APP in the cell (data not shown).

p(HGNC:BACE1) causesNoChange sec(a(HBP:"sAPP-alpha")) View Subject | View Object

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p(HGNC:BACE1) causesNoChange p(HGNC:APP) View Subject | View Object

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p(HGNC:BACE1, var("p.?")) causesNoChange sec(a(HBP:"sAPP-beta")) View Subject | View Object

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Evidence e6ae25ddaf
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However, while there is a significant increase in the production of CTFb in the presence of wild-type Asp 2, there is no increase in the presence of the mutant enzymes (Fig. 4b).

p(HGNC:BACE1) increases p(HGNC:APP, frag("672_770")) View Subject | View Object

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Evidence c813527d0c
JSON

In contrast to the expression of Asp 2, cathepsin D does not cause an increase in the secretion of sAPPb (Fig. 2d).

p(HGNC:CTSD) causesNoChange sec(a(HBP:"sAPP-beta")) View Subject | View Object

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Evidence 4040d4e2af
JSON

We have examined the distribution of Asp 2 in AD hippocampus using a polyclonal antiserum raised to a peptide sequence derived from Asp 2 (see Experimental Methods).We see clear neuronal staining but there is no staining associated with astrocytes, microglia, or oligodendrocytes (Figs. 5a and 5b).

path(MESH:"Alzheimer Disease") increases p(HGNC:BACE1) View Subject | View Object

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MeSH
Hippocampus

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