Genetic Deletion of Tumor Necrosis Factor-α Attenuates Amyloid-β Production and Decreases Amyloid Plaque Formation and Glial Response in the 5XFAD Model of Alzheimer’s Disease

2017 ◽  
Vol 60 (1) ◽  
pp. 165-181 ◽  
Author(s):  
Evi Paouri ◽  
Ourania Tzara ◽  
Sofia Zenelak ◽  
Spiros Georgopoulos
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Amyloid Β ◽  
Amyloid Plaque ◽  
Plaque Formation ◽  
Model Of Alzheimer’S Disease ◽  
Genetic Deletion ◽  
Factor Α ◽  
Necrosis Factor

scholarly journals Tumor Necrosis Factor-α–elicited Stimulation of γ-Secretase Is Mediated by c-Jun N-terminal Kinase-dependent Phosphorylation of Presenilin and Nicastrin

2008 ◽  
Vol 19 (10) ◽  
pp. 4201-4212 ◽  
Author(s):  
Lan-Hsin Kuo ◽  
Ming-Kuan Hu ◽  
Wen-Ming Hsu ◽  
Ying-Tsen Tung ◽  
Bo-Jeng Wang ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Phosphorylation Site ◽  
Amyloid Β ◽  
Site Directed Mutagenesis ◽  
Secretase Activity ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor

γ-Secretase is a multiprotein complex composed of presenilin (PS), nicastrin (NCT), Aph-1, and Pen-2, and it catalyzes the final proteolytic step in the processing of amyloid precursor protein to generate amyloid-β. Our previous results showed that tumor necrosis factor-α (TNF-α) can potently stimulate γ-secretase activity through a c-Jun N-terminal kinase (JNK)-dependent pathway. Here, we demonstrate that TNF-α triggers JNK-dependent serine/threonine phosphorylation of PS1 and NCT to stimulate γ-secretase activity. Blocking of JNK activity with a potent JNK inhibitor (SP600125) reduces TNF-α–triggered phosphorylation of PS1 and NCT. Consistent with this, we show that activated JNKs can be copurified with γ-secretase complexes and that active recombinant JNK2 can promote the phosphorylation of PS1 and NCT in vitro. Using site-directed mutagenesis and a synthetic peptide, we clearly show that the Ser319Thr320 motif in PS1 is an important JNK phosphorylation site that is critical for the TNF-α–elicited regulation of γ-secretase. This JNK phosphorylation of PS1 at Ser319Thr320 enhances the stability of the PS1 C-terminal fragment that is necessary for γ-secretase activity. Together, our findings strongly suggest that JNK is a critical intracellular mediator of TNF-α–elicited regulation of γ-secretase and governs the pivotal step in the assembly of functional γ-secretase.

scholarly journals Human Alzheimer and Inflammation Biomarkers after Anesthesia and Surgery

2011 ◽  
Vol 115 (4) ◽  
pp. 727-732 ◽  
Author(s):  
Junxia X. Tang ◽  
Dimitry Baranov ◽  
Mary Hammond ◽  
Leslie M. Shaw ◽  
Maryellen F. Eckenhoff ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Interleukin 6 ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Amyloid Β ◽  
Interleukin 10 ◽  
Neuroinflammatory Response ◽  
Total Tau ◽  
Factor Α ◽  
Necrosis Factor

Background The prevalence of postoperative cognitive disturbance, coupled with growing in vitro, cell, and animal evidence suggesting anesthetic effects on neurodegeneration, calls for additional study of the interaction between surgical care and Alzheimer neuropathology. The authors studied human cerebrospinal fluid (CSF) biomarkers during surgery. Methods Eleven patients undergoing idiopathic nasal CSF leak correction were admitted to this Institutional Review Board-approved study. Lumbar subarachnoid catheters were placed before the procedure. Anesthesia was total intravenous propofol or remifentanil or inhalational sevoflurane, depending on provider choice. CSF samples were taken after catheter placement (base), at procedure end (0 h), and then at 6, 24, and 48 h. CSF was analyzed using xMAP Luminex immunoassay (Luminex, Austin, TX). Results Of the 11 patients (age range, 53 ± 6 yr), 8 were women; 4 received intravenous anesthesia, 6 sevoflurane, and 1 mixed. Procedures lasted 6.4 ± 2 h. Mean CSF amyloid-β(1-42) remained unchanged, but total-tau and phosphorylated-tau181P increased progressively until at least 48 h. Total-tau, phosphorylated-tau, or amyloid-β(1-42) concentrations were not different between anesthetic groups. CSF interleukin-10, S100Beta, and tumor necrosis factor α were increased similarly in both anesthetic groups at 24 h, but interleukin-6 was increased more in the inhalational group. Conclusion These data indicate a robust neuroinflammatory response, including not only the usual markers (interleukin-6, tumor necrosis factor α, interleukin-10), but also S100Beta and tau, markers of injury. The total-tau/amyloid-β(1-42) ratio increased in a pattern consistent with Alzheimer disease, largely because of an increase in total-tau rather than a decline in amyloid-β(1-42). The differences in CSF interleukin-6 concentrations suggest that anesthetic management may make a difference in neuroinflammatory response.

Tumor necrosis factor α augments amyloid β protein (25–35) induced apoptosis in human cells

1997 ◽  
Vol 238 (1-2) ◽  
pp. 17-20 ◽  
Author(s):  
I Blasko ◽  
T.L Schmitt ◽  
E Steiner ◽  
K Trieb ◽  
B Grubeck-Loebenstein
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Amyloid Β ◽  
Human Cells ◽  
Amyloid Β Protein ◽  
Β Protein ◽  
Induced Apoptosis ◽  
Factor Α ◽  
Necrosis Factor
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