PMID- 25158693
OWN - NLM
STAT- MEDLINE
DCOM- 20150330
LR  - 20211203
IS  - 1742-2094 (Electronic)
IS  - 1742-2094 (Linking)
VI  - 11
DP  - 2014 Aug 27
TI  - Longitudinal follow-up of autophagy and inflammation in brain of APPswePS1dE9 
      transgenic mice.
PG  - 139
LID - 10.1186/s12974-014-0139-x [doi]
LID - 139
AB  - BACKGROUND: In recent years, studies have sought to understand the mechanisms 
      involved in the alteration of autophagic flux in Alzheimer's disease (AD). 
      Alongside the recent description of the impairment of lysosomal acidification, we 
      wanted to study the relationships between inflammation and autophagy, two 
      physiological components deregulated in AD. Therefore, a longitudinal study was 
      performed in APPswePS1dE9 transgenic mice at three, six and twelve months of age. 
      METHODS: Autophagic markers (Beclin-1, p62 and LC3) and the activation of 
      mammalian Target of Rapamycin (mTOR) signaling pathway were quantified by western 
      blot. Cytokine levels (IL-1beta, TNF-alpha and IL-6) were measured by ELISA. 
      Transmission electron microscopy was performed to detect autophagic vacuoles. 
      Mann-Whitney tests were used to compare wild-type (WT) versus APPswePS1dE9 mice. 
      Longitudinal changes in parameters were analyzed with a Kruskal-Wallis test 
      followed by a post-hoc Dunn's test. Correlation between two parameters was 
      assessed using a Spearman test. RESULTS: Compared to 12-month old WT mice, 
      12-month old APPswePS1dE9 mice had higher levels of IL-1beta and TNF-alpha, a greater 
      inhibition of the mTOR signaling pathway and lower levels of Beclin-1 expression 
      both in cortex and hippocampus. Regarding the relationship of the various 
      parameters in 12-month old APPswePS1dE9 mice, Beclin-1 rates were positively 
      correlated with IL-1beta and TNF-alpha levels. And, on the contrary, TNF-alpha levels were 
      inversely correlated with the levels of mTOR activation. Altogether, these 
      results suggest that inflammation could induce autophagy in APPswePS1dE9 mice. 
      However, these transgenic mice displayed a large accumulation of autophagic 
      vesicles within dystrophic neurons in cortex and hippocampus, indicating a 
      terminal failure in the autophagic process. CONCLUSIONS: This first demonstration 
      of relationships between inflammation and autophagy in in vivo models of AD 
      should be taken into account in new therapeutic strategies to prevent 
      inflammation and/or stimulate autophagy in advanced neurodegenerative process 
      such as AD.
FAU - Francois, Arnaud
AU  - Francois A
AD  - EA3808 molecular Targets and Therapeutic of Alzheimer's disease, University of 
      Poitiers, 1 Rue Georges Bonnet, 86073 Poitiers, TSA 51106, Cedex 9, France. 
      arnaudfrancois85@gmail.com.
FAU - Rioux Bilan, Agnes
AU  - Rioux Bilan A
FAU - Quellard, Nathalie
AU  - Quellard N
FAU - Fernandez, Beatrice
AU  - Fernandez B
FAU - Janet, Thierry
AU  - Janet T
FAU - Chassaing, Damien
AU  - Chassaing D
FAU - Paccalin, Marc
AU  - Paccalin M
FAU - Terro, Faraj
AU  - Terro F
FAU - Page, Guylene
AU  - Page G
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140827
PL  - England
TA  - J Neuroinflammation
JT  - Journal of neuroinflammation
JID - 101222974
RN  - 0 (Amyloid beta-Protein Precursor)
RN  - 0 (Apoptosis Regulatory Proteins)
RN  - 0 (Beclin-1)
RN  - 0 (Becn1 protein, mouse)
RN  - 0 (Cytokines)
RN  - 0 (Map1lc3b protein, mouse)
RN  - 0 (Microtubule-Associated Proteins)
RN  - 0 (PSEN1 protein, human)
RN  - 0 (Presenilin-1)
RN  - 0 (Receptors, Immunologic)
RN  - 0 (p62 natural killer cell receptor)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Amyloid beta-Protein Precursor/genetics
MH  - Animals
MH  - Apoptosis Regulatory Proteins/metabolism
MH  - Autophagy/*genetics
MH  - Beclin-1
MH  - Brain/metabolism/*pathology/ultrastructure
MH  - Cytokines/*metabolism
MH  - Disease Models, Animal
MH  - *Encephalitis/genetics/pathology/physiopathology
MH  - Female
MH  - Gene Expression Regulation/*genetics
MH  - Humans
MH  - Longitudinal Studies
MH  - Male
MH  - Mice
MH  - Mice, Transgenic
MH  - Microtubule-Associated Proteins/genetics/metabolism
MH  - Mutation/genetics
MH  - Presenilin-1/genetics
MH  - Receptors, Immunologic/metabolism
MH  - Signal Transduction/genetics
MH  - TOR Serine-Threonine Kinases/metabolism
PMC - PMC4154524
EDAT- 2014/08/28 06:00
MHDA- 2015/03/31 06:00
PMCR- 2014/08/27
CRDT- 2014/08/28 06:00
PHST- 2014/04/20 00:00 [received]
PHST- 2014/07/28 00:00 [accepted]
PHST- 2014/08/28 06:00 [entrez]
PHST- 2014/08/28 06:00 [pubmed]
PHST- 2015/03/31 06:00 [medline]
PHST- 2014/08/27 00:00 [pmc-release]
AID - s12974-014-0139-x [pii]
AID - 139 [pii]
AID - 10.1186/s12974-014-0139-x [doi]
PST - epublish
SO  - J Neuroinflammation. 2014 Aug 27;11:139. doi: 10.1186/s12974-014-0139-x.