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

APP and APLP1 are degraded through autophagy in response to proteasome inhibition in neuronal cells

Amyloid beta (Aβ) precursor protein (APP) is a key protein in the pathogenesis of Alzheimer’s disease (AD). Both APP and its paralogue APLP1 (amyloid beta precursor-like protein 1) have multiple functions in cell adhesion and proliferation. Previously it was thought that autophagy is a novel beta-amyloid peptide (Aβ)-generating pathway activated in AD. However, the protein proteolysis of APLP1 is still largely unknown. The present study shows that APLP1 is rapidly degraded in neuronal cells in response to stresses, such as proteasome inhibition. Activation of the endoplasmic reticulum (ER) stress by proteasome inhibitors induces autophagy, causing reduction of mature APLP1/APP. Blocking autophagy or JNK stress kinase rescues the protein expression for both APP and APLP1. Therefore, our results suggest that APP/APLP1 is degraded through autophagy and the APLP1 proteolysis is mainly mediated by autophagy-lysosome pathway