scholarly journals Phosphorylation of p66Shc and forkhead proteins mediates Aβ toxicity

2005 ◽  
Vol 169 (2) ◽  
pp. 331-339 ◽  
Author(s):  
Wanli W. Smith ◽  
Darrell D. Norton ◽  
Myriam Gorospe ◽  
Haibing Jiang ◽  
Shino Nemoto ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Redox Regulation ◽  
Critical Role ◽  
Ectopic Expression ◽  
Amyloid Β ◽  
Dominant Negative ◽  
Neuronal Cultures ◽  
Amyloid Β Peptide ◽  
Dependent Manner ◽  
Primary Neuronal Cultures

Excessive accumulation of amyloid β-peptide (Aβ) plays an early and critical role in synapse and neuronal loss in Alzheimer's Disease (AD). Increased oxidative stress is one of the mechanisms whereby Aβ induces neuronal death. Given the lessened susceptibility to oxidative stress exhibited by mice lacking p66Shc, we investigated the role of p66Shc in Aβ toxicity. Treatment of cells and primary neuronal cultures with Aβ caused apoptotic death and induced p66Shc phosphorylation at Ser36. Ectopic expression of a dominant-negative SEK1 mutant or chemical JNK inhibition reduced Aβ-induced JNK activation and p66Shc phosphorylation (Ser36), suggesting that JNK phosphorylates p66Shc. Aβ induced the phosphorylation and hence inactivation of forkhead transcription factors in a p66Shc-dependent manner. Ectopic expression of p66ShcS36A or antioxidant treatment protected cells against Aβ-induced death and reduced forkhead phosphorylation, suggesting that p66Shc phosphorylation critically influences the redox regulation of forkhead proteins and underlies Aβ toxicity. These findings underscore the potential usefulness of JNK, p66Shc, and forkhead proteins as therapeutic targets for AD.

A first-in-human phase I study of the oral Notch inhibitor LY900009 in patients with advanced cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3008-3008
Author(s):  
Shubham Pant ◽  
Suzanne Fields Jones ◽  
Carla Kurkjian ◽  
Jeffrey R. Infante ◽  
Kathleen N. Moore ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Advanced Cancer ◽  
Critical Role ◽  
Notch Pathway ◽  
Amyloid Β ◽  
Maximum Tolerated Dose ◽  
Amyloid Β Peptide ◽  
Dependent Manner ◽  
Gamma Secretase ◽  
Dose Dependent

3008 Background: Notch signaling plays a critical role during stem cell self-renewal and is deregulated in multiple human cancers. The Notch pathway may be activated inappropriately by receptor mutation and overexpression as well as aberrant signals from the tumor microenvironment. LY900009 is a selective small-molecule inhibitor of gamma secretase, the enzyme that cleaves and thereby activates Notch receptors. Methods: Dose escalation was performed in cohorts of 3 patients (pts) using a modified continual reassessment method. LY900009 was taken orally thrice weekly (every MWF) during a 28-day cycle. Safety, pharmacokinetic, pharmacodynamic, and clinical endpoints were evaluated. Results: 22 patients received LY900009 across 6 dose levels: 2mg (3pts), 4mg (4pts), 8mg (3pts), 15mg (3pts), 30mg (6pts), and 60mg (3pts). The most common treatment emergent adverse events possibly related to LY900009 across all grades included diarrhea (27%), vomiting (23%), nausea (18%), fatigue (23%), anorexia (23%), hypophosphatemia (14%), and rash (18%). Dose-limiting toxicities of fatigue/N/V (G3) and diarrhea (G3) were seen in 2 patients, respectively, treated at 60mg. The maximum tolerated dose (MTD) was tentatively identified at 30mg. After a single dose, mean Cmax increased from 4 to 158 ng/ml and mean AUC0-t(last) increased from 14 to 1160 ng-hr/ml. Both Cmax and AUC0-t(last) increased in a dose-dependent manner. Elimination half-life of LY900009 was approximately 2-3 hrs. LY900009 inhibited plasma levels of amyloid-β peptide (a downstream product of gamma secretase) in a dose-dependent manner with 80-90% inhibition observed in the 30 and 60mg cohorts. In the 15mg cohort, one patient had colonic biopsy that showed markedly increased glandular mucin consistent with pharmacologic inhibition of the Notch pathway. Two patients (10%) with leiomyosarcoma and ovarian cancer received 4 cycles of therapy. Conclusions: LY900009 demonstrates acceptable safety and pharmacokinetics in patients with advanced cancer. Pharmacodynamic endpoints show pathway inhibition at tolerable doses. One more cohort at 45mg is ongoing to refine the MTD and will be followed by an expansion cohort for patients with ovarian cancer.

scholarly journals Tau-tubulin kinase 1 and amyloid-β peptide induce phosphorylation of collapsin response mediator protein-2 and enhance neurite degeneration in Alzheimer disease mouse models

2019 ◽  
Author(s):  
Seiko Ikezu ◽  
Kaitlin L. Ingraham Dixie ◽  
Lacin Koro ◽  
Takashi Watanabe ◽  
Kozo Kaibuchi ◽  
...  
Keyword(s):  
Rho Kinase ◽  
Amyloid Β ◽  
Dominant Negative ◽  
Perforant Path ◽  
Amyloid Β Peptide ◽  
Dependent Manner ◽  
Collapsin Response Mediator Protein ◽  
Mediator Protein ◽  
Neurite Degeneration

AbstractThe accumulation of phosphorylated tau protein (pTau) in the entorhinal cortex (EC) is the earliest tau pathology in Alzheimer’s disease (AD). Tau tubulin kinase-1 (TTBK1) is a neuron-specific tau kinase and expressed in the EC and hippocampal regions in both human and mouse brains. Here we report that collapsin response mediator protein-2 (CRMP2), a critical mediator of growth cone collapse, is a new downstream target of TTBK1 and is accumulated in the EC region of early stage AD brains. TTBK1 transgenic mice show severe axonal degeneration in the perforant path, which is exacerbated by crossing with Tg2576 mice expressing Swedish familial AD mutant of amyloid precursor protein (APP). TTBK1 mice show accumulation of phosphorylated CRMP2 (pCRMP2), in the EC at 10 months of age, whereas age-matched APP/TTBK1 bigenic mice show pCRMP2 accumulation in both the EC and hippocampal regions. Amyloid-β peptide (Aβ) and TTBK1 suppresses the kinetics of microtubule polymerization and TTBK1 reduces the neurite length of primary cultured neurons in Rho kinase-dependent manner in vitro. Silencing of TTBK1 or expression of dominant-negative Rho kinase demonstrates that Aβ induces CRMP2 phosphorylation at threonine 514 in a TTBK1-dependent manner, and TTBK1 enhances Aβ-induced CRMP2 phosphorylation in Rho kinase-dependent manner in vitro. Furthermore, TTBK1 expression induces pCRMP2 complex formation with pTau in vitro, which is enhanced upon Aβ stimulation in vitro. Finally, pCRMP2 forms a complex with pTau in the EC tissue of TTBK1 mice in vivo, which is exacerbated in both the EC and hippocampal tissues in APP/TTBK1 mice. These results suggest that TTBK1 and Aβ synergistically induce phosphorylation of CRMP2, which may be causative for the neurite degeneration and somal accumulation of pTau in the EC neurons, indicating critical involvement of TTBK1 and pCRMP2 in the early AD pathology.

scholarly journals Oxidative Stress Induces Dephosphorylation of τ in Rat Brain Primary Neuronal Cultures

2002 ◽  
Vol 68 (4) ◽  
pp. 1590-1597 ◽  
Author(s):  
Daniel R. Davis ◽  
Brian H. Anderton ◽  
Jean-Pierre Brion ◽  
C. Hugh Reynolds ◽  
Diane P. Hanger
Keyword(s):  
Oxidative Stress ◽  
Rat Brain ◽  
Neuronal Cultures ◽  
Primary Neuronal Cultures

scholarly journals In vivo oxidative stress in brain of Alzheimer disease transgenic mice: Requirement for methionine 35 in amyloid β-peptide of APP

2010 ◽  
Vol 48 (1) ◽  
pp. 136-144 ◽  
Author(s):  
D. Allan Butterfield ◽  
Veronica Galvan ◽  
Miranda Bader Lange ◽  
Huidong Tang ◽  
Renã A. Sowell ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Alzheimer Disease ◽  
Transgenic Mice ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Methionine 35

scholarly journals Live Cell FRET Imaging Reveals Amyloid β-Peptide Oligomerization in Hippocampal Neurons

2021 ◽  
Author(s):  
Yang Gao ◽  
Stefan Wennmalm ◽  
Bengt Winblad ◽  
Sophia Schedin-Weiss ◽  
Lars Tjernberg
Keyword(s):  
Hippocampal Neurons ◽  
Resonance Energy Transfer ◽  
Amyloid Β ◽  
Resonance Energy ◽  
Live Cell ◽  
Amyloid Β Peptide ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Late Endosomes ◽  
Aβ Oligomerization

Amyloid β-peptide (Aβ) oligomerization is believed to contribute to the neuronal dysfunction in Alzheimer disease (AD). Despite decades of research, many details of Aβ oligomerization in neurons still need to be revealed. Förster Resonance Energy Transfer (FRET) is a simple but effective way to study molecular interactions. Here we use a confocal microscope with a sensitive Airyscan detector for FRET detection. By live cell FRET imaging, we detect Aβ42 oligomerization in primary neurons. The neurons were incubated with fluorescently labelled Aβ42 in the cell culture medium for 24 hours. Aβ42 were internalized and oligomerized into the lysosomes/late endosomes in a concentration-dependent manner. Both the cellular uptake and intracellular oligomerization of Aβ42 were significantly higher than for Aβ40. These findings provide a better understanding of Aβ42 oligomerization in neurons.

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