title: Longitudinal follow-up of autophagy and inflammation in brain of APPswePS1dE9 transgenic mice.
abstract: 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-1β, TNF-α 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-1β and TNF-α, 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-1β and TNF-α levels. And, on the contrary, TNF-α 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.
authors.affiliation: 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.
authors.forename: Arnaud
authors.initials: A
authors.lastname: François
authors.forename: Agnès
authors.initials: A
authors.lastname: Rioux Bilan
authors.forename: Nathalie
authors.initials: N
authors.lastname: Quellard
authors.forename: Béatrice
authors.initials: B
authors.lastname: Fernandez
authors.forename: Thierry
authors.initials: T
authors.lastname: Janet
authors.forename: Damien
authors.initials: D
authors.lastname: Chassaing
authors.forename: Marc
authors.initials: M
authors.lastname: Paccalin
authors.forename: Faraj
authors.initials: F
authors.lastname: Terro
authors.forename: Guylène
authors.initials: G
authors.lastname: Page
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000235:genetics*; D000071186:Beclin-1; D001921:Brain / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D004660:Encephalitis / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics*; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D053764:Presenilin-1 / Q000235:genetics; D011971:Receptors, Immunologic / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D016207:Cytokines; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D011971:Receptors, Immunologic; C431712:p62 natural killer cell receptor; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases