Intraperitoneal injection of JNK-specific inhibitor SP600125 inhibits the expression of presenilin-1 and Notch signaling in mouse brain without induction of apoptosis

Abstract

Presenilin-1 (PS1) is a multifunctional protein involved in many cellular functions including the processing of type 1 membrane proteins such as β-amyloid precursor protein (APP) and Notch 1 receptor. PS1 acts as the catalytic subunit of the γ-secretase complex, and participates in Notch 1 processing to release Notch intracellular domain (NICD) in the cytoplasm. NICD subsequently migrates to the nucleus and causes Notch signaling by increasing the expression of the Hes1 gene. We have previously shown that inhibition of basal activity of c-jun-NH2-terminal kinase (JNK) with JNK-specific inhibitor SP600125 represses the expression of PS1 and γ-secretase activity by increasing p53 level in SK-N-SH cell line in vitro(Lee and Das, 2008; Lee and Das, 2010). However, it is largely unknown whether PS1 can be effectively suppressed in vivo in adult mouse brains. In this report we showed that intraperitoneal (i.p) injection of JNK-specific inhibitor SP600125 decreased p-JNK level, and reduced PS1 expression by increasing p53 level in adult mouse brains. We also showed that suppression of PS1 expression by SP600125 reduced γ-secretase activity which decreased Notch 1 processing to reduce NICD in mouse brains. Furthermore, inhibition of Notch 1 processing by SP600125 decreased Notch 1 signaling by reducing the expression of the NICD target Hes1 gene in mouse brains without induction of apoptosis. These results provide insights for further study on PS1-mediated reduction of Notch 1 and APP processing for the treatment of Alzheimer’s disease.

Inhibition of c‐Jun N‐terminal kinase activation reverses Alzheimer disease phenotypes in APPswe/PS1dE9 mice

“…To understand the mechanisms underlying the beneficial effect of SP600125 treatment on Ab pathology, 3 endoproteolytic cleavage enzymes involved in modulating APP processing and Ab production were investigated. Consistent with the previous findings in vitro showing that active JNK is involved in the expression of BACE1 and PS1, [37][38][39][40] we proved that increased BACE1 and PS1 in the brains of vehicle-treated APPswe/PS1dE9 mice were markedly inhibited by SP600125 treatment down to the basal level of wild-type controls. More intriguingly, we also found that SP600125 treatment in APPswe/ PS1dE9 mice potently restored the decreased expression of ADAM10 up to the basal level of wild-type controls.…”

Prostaglandin I 2 upregulates the expression of anterior pharynx‐defective‐1α and anterior pharynx‐defective‐1β in amyloid precursor protein/presenilin 1 transgenic mice

“…(2008) supported this observation by showing that JNK‐dependent activation of γ‐secretase is responsible for Aβ deposition in H 2 O 2 ‐stimualted SH‐SY5Y cells. In detail, γ‐secretase as well as presenilin nicastrin is involved in mediating the effects of SP600125 on suppressing the production of Aβ 1–42 (Kuo et al ., 2008; Rahman et al ., 2012). More importantly, the inhibition of c‐Jun N‐terminal kinase activation reverses the AD phenotype in APP/PS1 mice (Zhou et al ., 2015).…”

Dynamics of Notch Pathway Expression during Mouse Testis Post-Natal Development and along the Spermatogenic Cycle

“…In the case of Hes1 and Hes5, only nuclear staining was considered positive, indicating activation of Notch signaling. The antibodies for the Notch components and effectors were previously validated by others in the mouse (anti-Notch1 [29], anti-Notch3 [30], anti-Dll1, [31] anti-Dll4, [31] anti-Jagged1, [32] anti-Hes1 [33] and anti-Hes5 [34]) and rat species (anti-Notch2 [35]). Except for Notch1, all antibodies were polyclonal and the different lots used were originated from different animals (according to manufacturers).…”