scholarly journals 3K3A-activated protein C blocks amyloidogenic BACE1 pathway and improves functional outcome in mice

2019 ◽  
Vol 216 (2) ◽  
pp. 279-293 ◽  
Author(s):  
Divna Lazic ◽  
Abhay P. Sagare ◽  
Angeliki M. Nikolakopoulou ◽  
John H. Griffin ◽  
Robert Vassar ◽  
...  
Keyword(s):  
Protein C ◽  
Early Stage ◽  
Activated Protein C ◽  
Amyloid Β ◽  
Transcriptional Inhibition ◽  
Model Of Alzheimer’S Disease ◽  
Prevention Therapy ◽  
A Cell ◽  
Aβ Generation ◽  
5Xfad Mice

3K3A-activated protein C (APC), a cell-signaling analogue of endogenous blood serine protease APC, exerts vasculoprotective, neuroprotective, and anti-inflammatory activities in rodent models of stroke, brain injury, and neurodegenerative disorders. 3K3A-APC is currently in development as a neuroprotectant in patients with ischemic stroke. Here, we report that 3K3A-APC inhibits BACE1 amyloidogenic pathway in a mouse model of Alzheimer’s disease (AD). We show that a 4-mo daily treatment of 3-mo-old 5XFAD mice with murine recombinant 3K3A-APC (100 µg/kg/d i.p.) prevents development of parenchymal and cerebrovascular amyloid-β (Aβ) deposits by 40–50%, which is mediated through NFκB–dependent transcriptional inhibition of BACE1, resulting in blockade of Aβ generation in neurons overexpressing human Aβ-precursor protein. Consistent with reduced Aβ deposition, 3K3A-APC normalized hippocampus-dependent behavioral deficits and cerebral blood flow responses, improved cerebrovascular integrity, and diminished neuroinflammatory responses. Our data suggest that 3K3A-APC holds potential as an effective anti-Aβ prevention therapy for early-stage AD.

Activated protein C inhibits amyloid β production via promoting expression of ADAM-10

2014 ◽  
Vol 1545 ◽  
pp. 35-44 ◽  
Author(s):  
Bing Li ◽  
Dawei Yu ◽  
Zhiying Xu
Keyword(s):  
Protein C ◽  
Activated Protein C ◽  
Amyloid Β

Enhancement by Activated Protein C of tPA-induced Lysis in a Cell-free System

1987 ◽  
Author(s):  
J C Fredenburgh ◽  
D Collen ◽  
M E Nesheim
Keyword(s):  
Protein C ◽  
Activated Protein C ◽  
Protein S ◽  
Plasminogen Activation ◽  
Free System ◽  
Cell Free System ◽  
Normal Plasma ◽  
Lysis Time ◽  
A Cell

The profibrinolytic activity of human activated protein C (APC) was studied in a cell-free system using human plasma. Normal and Ba+* citrate adsorbed human plasmas were dialyzed against 150mM NaCl, 20mM Hepes, pH 7.4 and diluted to an A280 of 16. Reactions were initiated by the addition of aliquots of plasma to cuvettes containing human melanoma tPA and human thrombin at final concentrations of 1 and 30nM, respectively. The effects of Ca+* and varying concentrations of APC on clotlysis times were examined by monitoring turbidity at 600nM while maintaining the temperature at 37°C. The lysis time, defined as the midpoint of turbidity change, was 128 min for normal plasma containing 10 mM Ca+* and showed progressive and saturable shortening to about 90 min at > 50nM APC. In the absence of Ca+*, lysis time was 55 min for normal plasma and did not shorten in response to APC. With Ba+* citrate adsorbed plasma, the lysis time was 82 min in the presence of 10mM Ca+*, and shortened to 42 min without Ca+*. APC had no effect on lysis time in Ba+* adsorbed plasma either with or without Ca+*. Both bovine and human APC were equally potent. Electrophoresis in DodSO4 and autoradiography of plasma samples containing 125I-labelled plasminogen indicated enhanced rates of plasminogen activation in the presence of APC. These data indicate that APC decreases lysis time in vitro at the level of plasminogen activation. This effect is dependent on Ca+* and may involve additional vitamin K-dependent protein ( s).

Effects of adjuvant chemotherapy on the protein C anticoagulant pathway in patients with early stage breast cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 8563-8563 ◽  
Author(s):  
S. D. Mukherjee ◽  
M. Levine ◽  
S. Beaudin ◽  
L. Shin ◽  
S. Caruso ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Protein C ◽  
Early Stage ◽  
Activated Protein C ◽  
Early Stage Breast Cancer ◽  
Breast Cancer Patients ◽  
Endothelial Protein C Receptor ◽  
Increased Risk ◽  
Chemotherapy Agents ◽  
Endothelial Receptor

8563 Background: Although chemotherapy treatment is associated with an increased risk of thrombosis, the pathogenic mechanisms are poorly understood. We have previously shown that treatment of endothelial cells with adriamycin and epirubicin impairs the protein C anticoagulant pathway by downregulating EPCR (endothelial protein C receptor), an endothelial receptor required for the conversion of protein C to the anticoagulant enzyme activated protein C (APC). In this study, we examined the effects of adriamycin- and epirubicin-containing chemotherapy on the protein C anticoagulant pathway in early stage breast cancer patients. Methods: We collected blood samples from 20 patients patients with early stage breast cancer undergoing adjuvant CEF (cyclophosphamide, epirubicin and 5-fluorouracil) or CMF (cyclophosphamide, methotrexate and 5-fluorouracil) chemotherapy on days 1, 2 and 8 for the first 2 cycles of treatment. Markers of protein C generation (protein C, thrombin-antithrombin (TAT) complexes, and APC) were measured on these days. Results: Plasma protein C levels were significantly lower at cycle 2 day 8 (0.88 ± 0.14 U/ml) compared to pre-chemotherapy levels (1.07 ± 0.23 U/ml) (p=0.0036). Plasma TAT levels were significantly higher at cycle 2 day 8 (2.87 ± 0.79 μg/L) compared to pre-chemotherapy levels (2.01 ± 1.24 μg/L) (p=0.02). Based on the APC levels, the patients appear to fall into two categories in terms of their ability to generate APC. The first group (n=16) has elevated APC levels that parallel the elevated TAT levels, whereas the second group (n=4) has low APC levels despite elevated TAT levels. Conclusions: Impaired ability to generate APC in a subpopulation of patients may reflect chemotherapy-induced impairment of the protein C pathway through the downregulation of EPCR. This pilot study provides new mechanistic insights into the prothrombotic effects of chemotherapy agents. No significant financial relationships to disclose.

scholarly journals Caspase-6 Knockout in the 5xFAD Model of Alzheimer’s Disease Reveals Favorable Outcome on Memory and Neurological Hallmarks

2020 ◽  
Vol 21 (3) ◽  
pp. 1144
Author(s):  
Ariel Angel ◽  
Rotem Volkman ◽  
Tabitha Grace Royal ◽  
Daniel Offen
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Neurodegenerative Disorder ◽  
Amyloid Β ◽  
Cysteine Proteases ◽  
Knock Out ◽  
Model Of Alzheimer’S Disease ◽  
Caspase 6 ◽  
5Xfad Mice

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and is the most common form of dementia in the elderly. Caspases, a family of cysteine proteases, are major mediators of apoptosis and inflammation. Caspase-6 is considered to be an up-stream modulator of AD pathogenesis as active caspase-6 is abundant in neuropil threads, neuritic plaques, and neurofibrillary tangles of AD brains. In order to further elucidate the role of caspase-6 activity in the pathogenesis of AD, we produced a double transgenic mouse model, combining the 5xFAD mouse model of AD with caspase-6 knock out (C6-KO) mice. Behavioral examinations of 5xFAD/C6-KO double transgenic mice showed improved performance in spatial learning, memory, and anxiety/risk assessment behavior, as compared to 5xFAD mice. Hippocampal mRNA expression analyses showed significantly reduced levels of inflammatory mediator TNF-α, while the anti-inflammatory cytokine IL-10 was increased in 5xFAD/C6-KO mice. A significant reduction in amyloid-β plaques could be observed and immunohistochemistry analyses showed reduced levels of activated microglia and astrocytes in 5xFAD/C6-KO, compared to 5xFAD mice. Together, these results indicate a substantial role for caspase-6 in the pathology of the 5xFAD model of AD and suggest further validation of caspase-6 as a potential therapeutic target for AD.

Accelerated Aβ Generation in a Cell Model of Alzheimer's Disease-related Endosomal–Lysosomal System Upregulation

2003 ◽  
pp. 461-467
Author(s):  
Paul M. Mathews ◽  
Carolyn B. Guerra ◽  
Ying Jiang ◽  
Benjamin H. Kao ◽  
Ravi Dinakar ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Model ◽  
Model Of Alzheimer’S Disease ◽  
A Cell ◽  
Lysosomal System ◽  
Aβ Generation

scholarly journals Inhibitory Neural Network’s Impairments at Hippocampal CA1 LTP in an Aged Transgenic Mouse Model of Alzheimer’s Disease

2021 ◽  
Vol 22 (2) ◽  
pp. 698
Author(s):  
Hyeon Jeong Seo ◽  
Jung Eun Park ◽  
Seong-Min Choi ◽  
Taekyoung Kim ◽  
Soo Hyun Cho ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Signal Transmission ◽  
Amyloid Β ◽  
Neuronal Loss ◽  
Long Term Potentiation ◽  
Model Of Alzheimer’S Disease ◽  
5Xfad Mice ◽  
The Impact

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by a rapid accumulation of amyloid β (Aβ) protein in the hippocampus, which impairs synaptic structures and neuronal signal transmission, induces neuronal loss, and diminishes memory and cognitive functions. The present study investigated the impact of neuregulin 1 (NRG1)-ErbB4 signaling on the impairment of neural networks underlying hippocampal long-term potentiation (LTP) in 5xFAD mice, a model of AD with greater symptom severity than that of TG2576 mice. Specifically, we observed parvalbumin (PV)-containing hippocampal interneurons, the effect of NRG1 on hippocampal LTP, and the functioning of learning and memory. We found a significant decrease in the number of PV interneurons in 11-month-old 5xFAD mice. Moreover, synaptic transmission in the 5xFAD mice decreased at 6 months of age. The 11-month-old transgenic AD mice showed fewer inhibitory PV neurons and impaired NRG1-ErbB4 signaling than did wild-type mice, indicating that the former exhibit the impairment of neuronal networks underlying LTP in the hippocampal Schaffer-collateral pathway. In conclusion, this study confirmed the impaired LTP in 5xFAD mice and its association with aberrant NRG1-ErbB signaling in the neuronal network.

Protective effects of activated protein C in sepsis

2008 ◽  
Vol 100 (10) ◽  
pp. 582-592 ◽  
Author(s):  
Lisa J. Toltl ◽  
Laura L. Swystun ◽  
Laura Pepler ◽  
Patricia C. Liaw
Keyword(s):  
Host Response ◽  
Protein C ◽  
Clinical Success ◽  
Activated Protein C ◽  
Endothelial Permeability ◽  
Protective Effects ◽  
Preclinical Research ◽  
The Past ◽  
A Cell ◽  
Barrier Breakdown

SummarySepsis remains a complex syndrome associated with significant morbidity and mortality. It is now widely accepted that the pathways of inflammation, coagulation, apoptosis, and endothelial permeability are intimately linked in sepsis pathophysiology. The clinical success of activated protein C (APC), a natural anticoagulant, in reducing mortality in patients with severe sepsis has fuelled basic and preclinical research on the protective effects of this molecule. Over the past 15 years, impressive research advances have provided novel insights into the multifunctional activities of APC. APC is now viewed not only as an anticoagulant, but also as a cell signaling molecule that dampens the excessive or insufficiently controlled host response during sepsis. This review attempts to summarize the pleiotropic activities of APC with focus on its ability to inhibit coagulation, inflammation, apoptosis, and endothelial barrier breakdown. A comprehensive PUBMED literature review up to May 2008 was conducted.

Activated protein C: the cure for sepsis - again?

Anaesthesia ◽  
2001 ◽  
Vol 56 (12) ◽  
pp. 1133-1135 ◽  
Author(s):  
Tariq Hoth ◽  
Timothy W. Evans
Keyword(s):  
Protein C ◽  
Activated Protein C
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