a(HBP:"sAPP-beta")

Entity

Name

sAPP-beta

Namespace

HBP

Namespace Version

20181023

Namespace URL

https://raw.githubusercontent.com/pharmacome/terminology/3074b85b858455d8eeb76cfcdef685ced19bbe11/export/hbp-names.belns

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). PubMed:10656250

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). PubMed:10656250

In contrast to the expression of Asp 2, cathepsin D does not cause an increase in the secretion of sAPPb (Fig. 2d). PubMed:10656250

BI-3 also potentially inhibited the release of sAPPb (IC50 = 0.5 mM) and sAPPa (IC50 = 3.4 mM, Figs. 2B and 3B). BI- 4, which is short peptide of BI-3, showed no effects on sAPP secretion. PubMed:17293005

Taken together, these results show that BI-1 and BI-3 not only selectively reduce the level of APPbeta but also lead to the accumulation of APPalpha in cells with no change of full-length APP level. PubMed:17293005

BI-3 also potentially inhibited the release of sAPPb (IC50 = 0.5 mM) and sAPPa (IC50 = 3.4 mM, Figs. 2B and 3B). BI- 4, which is short peptide of BI-3, showed no effects on sAPP secretion. PubMed:17293005

BI-1 treatment dose-dependently inhibited the release of both sAPPa and sAPPb in the conditioned medium (Figs. 2A and 3A). The 50% inhibitory concentrations (IC50) of BI-1 were about 1.5 mM for sAPPa and 0.9 mM for APPb, respectively. But BI-2, which is mainly composed of the core region BACE1 69–73, did not show the inhibitory effects PubMed:17293005

Taken together, these results show that BI-1 and BI-3 not only selectively reduce the level of APPbeta but also lead to the accumulation of APPalpha in cells with no change of full-length APP level. PubMed:17293005

BI-1 treatment dose-dependently inhibited the release of both sAPPa and sAPPb in the conditioned medium (Figs. 2A and 3A). The 50% inhibitory concentrations (IC50) of BI-1 were about 1.5 mM for sAPPa and 0.9 mM for APPb, respectively. But BI-2, which is mainly composed of the core region BACE1 69–73, did not show the inhibitory effects PubMed:17293005

Nicotine stimulates the secretion of betaAPP, which is trophic and neuroprotective against Abeta, from PC12 cells through an alpha7 and calcium-dependent pathway (Kim et al., 1997) as well as increasing the secretion of soluble APP and lowering the Abeta-containing sAPP-gamma in rats (Lahiri et al., 2002), again through nAChR-dependent mechanisms. Galantamine, a nAChR potentiator and AChE inhibitor, also increases the secretion of sAPP from human SH-SY5Y neuroblastoma cells (Lenzken et al., 2007) through the activation of nAChRs. It therefore seems that activation of nAChRs shifts the balance of APP processing away from beta-amyloidogenic to soluble APP production. PubMed:19293145

Nicotine stimulates the secretion of betaAPP, which is trophic and neuroprotective against Abeta, from PC12 cells through an alpha7 and calcium-dependent pathway (Kim et al., 1997) as well as increasing the secretion of soluble APP and lowering the Abeta-containing sAPP-gamma in rats (Lahiri et al., 2002), again through nAChR-dependent mechanisms. Galantamine, a nAChR potentiator and AChE inhibitor, also increases the secretion of sAPP from human SH-SY5Y neuroblastoma cells (Lenzken et al., 2007) through the activation of nAChRs. It therefore seems that activation of nAChRs shifts the balance of APP processing away from beta-amyloidogenic to soluble APP production. PubMed:19293145

Abeta, an important player in AD, is derived from beta-amyloid precursor protein (APP) through sequential cleavages by beta- and gamma-secretases: APP is cleaved by beta-secretase (BACE1) to generate the large secreted derivative sAPPbeta and the membrane-bound APP C-terminal fragment-beta; the latter can be further cleaved by gamma-secretase to generate Abeta and APP intracellular domain. Alternatively, APP can be cleaved by alpha-secretase within the Abeta domain, which precludes Abeta production and instead generates secreted sAPPalpha that has been shown to be neuroprotective PubMed:24590577

Nicotine stimulates the secretion of betaAPP, which is trophic and neuroprotective against Abeta, from PC12 cells through an alpha7 and calcium-dependent pathway (Kim et al., 1997) as well as increasing the secretion of soluble APP and lowering the Abeta-containing sAPP-gamma in rats (Lahiri et al., 2002), again through nAChR-dependent mechanisms. Galantamine, a nAChR potentiator and AChE inhibitor, also increases the secretion of sAPP from human SH-SY5Y neuroblastoma cells (Lenzken et al., 2007) through the activation of nAChRs. It therefore seems that activation of nAChRs shifts the balance of APP processing away from beta-amyloidogenic to soluble APP production. PubMed:19293145