Modulation of Aβ42 in vivo by γ-secretase modulator in primates and humans

10.1186/s13195-015-0137-yAlzheimer's Research and Therapy715

γ-Secretase Modulators and APH1 Isoforms Modulate γ-Secretase Cleavage but Not Position of ε-Cleavage of the Amyloid Precursor Protein (APP)

10.1371/journal.pone.0144758PLoS ONE1012e014475

Notch1 Augments NF- ĸB Activity by Facilitating its Nuclear Retention

Notch1 specifically upregulates expression of the cytokine interferon-gamma in peripheral T cells through activation of NF-kappaB. However, how Notch mediates NF-kappaB activation remains unclear. Here, we examined the temporal relationship between Notch signaling and NF-kappaB induction during T-cell activation. NF-kappaB activation occurs within minutes of T-cell receptor (TCR) engagement and this activation is sustained for at least 48 h following TCR signaling. We used gamma-secretase inhibitor (GSI) to prevent the cleavage and subsequent activation of Notch family members. We demonstrate that GSI blocked the later, sustained NF-kappaB activation, but did not affect the initial activation of NF-kappaB. Using biochemical approaches, as well as confocal microscopy, we show that the intracellular domain of Notch1 (N1IC) directly interacts with NF-kappaB and competes with IkappaBalpha, leading to retention of NF-kappaB in the nucleus. Additionally, we show that N1IC can directly regulate IFN-gamma expression through complexes formed on the IFN-gamma promoter. Taken together, these data suggest that there are two \u27waves\u27 of NF-kappaB activation: an initial, Notch-independent phase, and a later, sustained activation of NF-kappaB, which is Notch dependent

Independent Relationship between Amyloid Precursor Protein (APP) Dimerization and γ-Secretase Processivity

10.1371/journal.pone.0111553PLoS ONE910e11155

Cholestenoic acid, an endogenous cholesterol metabolite, is a potent ?-secretase modulator

10.1186/s13024-015-0021-zMolecular Neurodegeneration1012

Dishevelled regulates the metabolism of amyloid precursor protein via protein kinase C/Mitogen-activated protein kinase and c-Jun terminal kinase

Alzheimer’s disease (AD) is a disorder of two pathologies: amyloid plaques, the core of which is a peptide derived from the amyloid precursor protein (APP), and neurofibrillary tangles composed of highly phosphorylated tau. Protein kinase C (PKC)is known to increase non-amyloidogenic a-secretase cleavage of APP, producing secreted APP (sAPPa), and glycogen synthasekinase (GSK)-3b is known to increase tau phosphorylation. Both PKC and GSK-3b are components of the wnt signaling cascade. Here we demonstrate that overexpression of another member of this pathway, dishevelled (dvl-1), increasess APPa production. The dishevelled action on APP is mediated via both c-jun terminal kinase (JNK) and protein kinase C(PKC)/mitogen-activated protein (MAP) kinase but not via p38MAP kinase. These data position dvl-1 upstream of both PKCand JNK, thereby explaining the previously observed dual signaling action of dvl-1. Furthermore, we show that human dvl-1and wnt-1 also reduce the phosphorylation of tau by GSK-3b. Therefore, both APP metabolism and tau phosphorylation are potentially linked through wnt signaling