Longitudinal follow-up of autophagy and inflammation in brain of APPswePS1dE9 transgenic mice

Journal of Neuroinflammation

Guylène Page⁴  Faraj Terro²  Marc Paccalin³  Damien Chassaing⁴  Thierry Janet⁴  Béatrice Fernandez¹  Nathalie Quellard¹  Agnès Rioux Bilan⁴  Arnaud François⁴ 

[1] Pathology Department, Poitiers University Hospital, Poitiers F-86021, France;Service d¿histologie et de cytogénétique, Hôpital de la Mère et de l¿Enfant, Limoges F-87025, France;CIC-P 1402, Poitiers University Hospital, Poitiers F-86021, France;EA3808 molecular Targets and Therapeutic of Alzheimer¿s disease, University of Poitiers, 1 Rue Georges Bonnet, 86073 Poitiers, TSA 51106, Cedex 9, France

关键词: Transgenic mouse model;    TNF-?;    IL-1?;    Beclin-1;    Alzheimer;   

Others  :  1151069
DOI  :  10.1186/s12974-014-0139-x

 received in 2014-04-20, accepted in 2014-07-28,  发布年份 2014

【 摘 要 】

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-1?, TNF-? 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-1? and TNF-?, 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-1? and TNF-? levels. And, on the contrary, TNF-? 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.

【 授权许可】

   
2014 François et al.; licensee BioMed Central Ltd.

【 图 表 】

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