PMID- 28826177
OWN - NLM
STAT- MEDLINE
DCOM- 20180507
LR  - 20180507
IS  - 1875-8908 (Electronic)
IS  - 1387-2877 (Linking)
VI  - 60
IP  - 1
DP  - 2017
TI  - Genetic Deletion of Tumor Necrosis Factor-alpha Attenuates Amyloid-beta Production and 
      Decreases Amyloid Plaque Formation and Glial Response in the 5XFAD Model of 
      Alzheimer's Disease.
PG  - 165-181
LID - 10.3233/JAD-170065 [doi]
AB  - Increasing evidence suggests that neuroinflammation comprises a major 
      characteristic of Alzheimer's disease (AD). Tumor necrosis factor-alpha (TNF-alpha) is a 
      pleiotropic pro-inflammatory cytokine implicated in neurodegenerative diseases 
      including AD, and has been proposed as a potent therapeutic target for AD. 
      Although a number of studies focusing on pharmacological or genetic manipulation 
      of TNF-alpha and its receptors in AD mice have provided significant knowledge 
      regarding the role of TNF-alpha signaling pathway in the pathogenesis of AD, the 
      consequences of TNF-alpha genetic deletion have not been thoroughly examined. Here, 
      we focused on the effect of TNF-alpha deficiency on the amyloid phenotype of 5XFAD 
      mice. Our analysis revealed that amyloid deposition, amyloid-beta (Abeta) levels, and 
      AbetaPP-carboxyterminal fragments are significantly reduced in the brains of 
      5XFAD/TNF-alpha-/- mice compared to the 5XFAD/TNF-alpha+/+. We found decreased protein 
      levels of beta- and alpha-secretases in the 5XFAD/TNF-alpha-/- brains, suggesting for an 
      effect of TNF-alpha on AbetaPP processing and Abeta generation. We also show for the first 
      time that TNF-alpha affects PS1in vivo, as 5XFAD mice lacking TNF-alpha expression 
      display reduced PS1-carboxyterminal fragments implying for diminished PS1 
      activity. Moreover, TNF-alpha deficiency decreases microglial and astrocytic 
      activation and significantly restricts the phagocytic activity of macrophages 
      against Abeta, supporting for reduced responsiveness of phagocytes toward Abeta. 
      Overall, our results reveal that TNF-alpha genetic deletion in 5XFAD mice attenuates 
      amyloid plaque formation by lowering Abeta generation through the reduction of 
      functionally active PS1 and beta-secretase rather than promoting Abeta clearance by 
      phagocytic cells. Our data further suggest TNF-alpha inhibition as a therapeutic 
      approach for AD.
FAU - Paouri, Evi
AU  - Paouri E
AD  - Laboratory of Cellular Neurobiology, Center of Basic Research, Biomedical 
      Research Foundation, Academy of Athens, Athens, Greece.
FAU - Tzara, Ourania
AU  - Tzara O
AD  - Laboratory of Cellular Neurobiology, Center of Basic Research, Biomedical 
      Research Foundation, Academy of Athens, Athens, Greece.
FAU - Zenelak, Sofia
AU  - Zenelak S
AD  - Laboratory of Cellular Neurobiology, Center of Basic Research, Biomedical 
      Research Foundation, Academy of Athens, Athens, Greece.
FAU - Georgopoulos, Spiros
AU  - Georgopoulos S
AD  - Laboratory of Cellular Neurobiology, Center of Basic Research, Biomedical 
      Research Foundation, Academy of Athens, Athens, Greece.
LA  - eng
PT  - Journal Article
PL  - Netherlands
TA  - J Alzheimers Dis
JT  - Journal of Alzheimer's disease : JAD
JID - 9814863
RN  - 0 (Aif1 protein, mouse)
RN  - 0 (Amyloid beta-Peptides)
RN  - 0 (CD11b Antigen)
RN  - 0 (Calcium-Binding Proteins)
RN  - 0 (Glial Fibrillary Acidic Protein)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Membrane Proteins)
RN  - 0 (Microfilament Proteins)
RN  - 0 (Presenilin-1)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 3.4.- (Amyloid Precursor Protein Secretases)
RN  - EC 3.4.23.- (Aspartic Acid Endopeptidases)
RN  - EC 3.4.23.46 (Bace1 protein, mouse)
RN  - EC 3.4.24.81 (ADAM10 Protein)
RN  - EC 3.4.24.81 (Adam10 protein, mouse)
SB  - IM
MH  - ADAM10 Protein/metabolism
MH  - Alzheimer Disease/genetics/*pathology
MH  - Amyloid Precursor Protein Secretases/genetics/metabolism
MH  - Amyloid beta-Peptides/*metabolism
MH  - Animals
MH  - Aspartic Acid Endopeptidases/genetics/metabolism
MH  - Brain/pathology
MH  - CD11b Antigen/metabolism
MH  - Calcium-Binding Proteins/metabolism
MH  - Cells, Cultured
MH  - Disease Models, Animal
MH  - Gene Expression Regulation/*genetics
MH  - Glial Fibrillary Acidic Protein/metabolism
MH  - Lipopolysaccharides/pharmacology
MH  - Macrophages/drug effects/metabolism
MH  - Membrane Proteins/metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Microfilament Proteins/metabolism
MH  - Neuroglia/*metabolism
MH  - Presenilin-1/genetics/metabolism
MH  - Tumor Necrosis Factor-alpha/*genetics/metabolism
OTO - NOTNLM
OT  - 5XFAD
OT  - Alzheimer's disease
OT  - TNF-alpha
OT  - amyloid-beta
OT  - glia
OT  - mouse models
OT  - neuroinflammation
OT  - presenilin-1
OT  - beta-secretase
EDAT- 2017/08/23 06:00
MHDA- 2018/05/08 06:00
CRDT- 2017/08/23 06:00
PHST- 2017/08/23 06:00 [pubmed]
PHST- 2018/05/08 06:00 [medline]
PHST- 2017/08/23 06:00 [entrez]
AID - JAD170065 [pii]
AID - 10.3233/JAD-170065 [doi]
PST - ppublish
SO  - J Alzheimers Dis. 2017;60(1):165-181. doi: 10.3233/JAD-170065.