a(HBP:"sAPP-alpha")

Entity

Name

sAPP-alpha

Namespace

HBP

Namespace Version

20181023

Namespace URL

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

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

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

Surprisingly, BI-1 treatment resulted in a drastic, dose-dependent increase in the level of intracellular APPa (Figs. 2A and 3A). BI-3 also induced the accumulation of intracellular APPa until the concentration of BI-3 was raised to 12.5 mM; however, treatment of BI-3 with 25 mM decreased the level of intracellular APPa. 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

Surprisingly, BI-1 treatment resulted in a drastic, dose-dependent increase in the level of intracellular APPa (Figs. 2A and 3A). BI-3 also induced the accumulation of intracellular APPa until the concentration of BI-3 was raised to 12.5 mM; however, treatment of BI-3 with 25 mM decreased the level of intracellular APPa. 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

Recent drug discovery efforts in our group have yielded novel M1-selective PAMs VU0405652 (ML169) and VU0456940, both of which potentiate M1-mediated non-amyloidogenic amyloid precursor protein (APPsalpha) processing, suggesting disease-modifying potential in AD PubMed:24511233

Moreover, AF102B administration decreased the total CSF Abeta levels by 22% in 14 of 19 AD patients without affecting sAPPalpha levels. However, AF102B has serious side effects including gastrointestinal symptoms, diaphoresis, confusion, diarrhea, and asthenia PubMed:24590577

Another M1 mAChR-selective agonist, talsaclidine, enhances nonamyloidogenic processing of APP, resulting in increased sAPPalpha release from both a transfected human astrocytoma cell line and rat brain slices in a dose-dependent manner, as well as significantly decreasing CSF Abeta in AD patients[111]. However, talsaclidine at high doses had several side-effects such as sweating and salivation PubMed:24590577

Interestingly, stimulation of M1 mAChR by agonists has been found to enhance sAPPalpha generation and reduce Abeta production[61-70]. Protein kinase C (PKC) is well-known to be activated upon stimulation of M1 mAChR. PKC may promote the activity of alpha-secretase[71] and the traffi cking of APP from the Golgi/ trans-Golgi network to the cell surface PubMed:24590577

In fact, Abeta has been shown to induce the uncoupling of M1 mAChR from G-protein, antagonizing the function of M1 mAChR under the pathological conditions of AD[96, 97]. Such an uncoupling may result in decreased signal transduction, reduced levels of sAPPalpha, and increased production of Abeta, triggering a vicious cycle. PubMed:24590577

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

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