| First Author | Qian Y | Year | 2016 |
| Journal | J Neuroinflammation | Volume | 13 |
| Issue | 1 | Pages | 145 |
| PubMed ID | 27287266 | Mgi Jnum | J:285076 |
| Mgi Id | MGI:6392985 | Doi | 10.1186/s12974-016-0598-3 |
| Citation | Qian Y, et al. (2016) Neuronal seipin knockout facilitates Abeta-induced neuroinflammation and neurotoxicity via reduction of PPARgamma in hippocampus of mouse. J Neuroinflammation 13(1):145 |
| abstractText | BACKGROUND: A characteristic phenotype of congenital generalized lipodystrophy 2 (CGL2) that is caused by loss-of-function of seipin gene is mental retardation. Seipin is highly expressed in hippocampal pyramidal cells and astrocytes. Neuronal knockout of seipin in mice (seipin-KO mice) reduces the hippocampal peroxisome proliferator-activated receptor gamma (PPARgamma) level without the loss of pyramidal cells. The down-regulation of PPARgamma has gained increasing attention in neuroinflammation of Alzheimer's disease (AD). Thus, the present study focused on exploring the influence of seipin depletion on beta-amyloid (Abeta)-induced neuroinflammation and Abeta neurotoxicity. METHODS: Adult male seipin-KO mice were treated with a single intracerebroventricular (i.c.v.) injection of Abeta25-35 (1.2 nmol/mouse) or Abeta1-42 (0.1 nmol/mouse), generally a non-neurotoxic dose in wild-type (WT) mice. Spatial cognitive behaviors were assessed by Morris water maze and Y-maze tests, and hippocampal CA1 pyramidal cells and inflammatory responses were examined. RESULTS: The Abeta25-35/1-42 injection in the seipin-KO mice caused approximately 30-35 % death of pyramidal cells and production of Hoechst-positive cells with the impairment of spatial memory. In comparison with the WT mice, the number of astrocytes and microglia in the seipin-KO mice had no significant difference, whereas the levels of IL-6 and TNF-alpha were slightly increased. Similarly, the Abeta25-35/1-42 injection in the seipin-KO mice rather than the WT mice could stimulate the activation of astrocytes or microglia and further elevated the levels of IL-6 and TNF-alpha. Treatment of the seipin-KO mice with the PPARgamma agonist rosiglitazone (rosi) could prevent Abeta25-35/1-42-induced neuroinflammation and neurotoxicity, which was blocked by the PPARgamma antagonist GW9962. In the seipin-KO mice, the level of glycogen synthase kinase-3beta (GSK3beta) phosphorylation at Tyr216 was elevated, while at Ser9, it was reduced compared to the WT mice, which were corrected by the rosi treatment but were unaffected by the Abeta25-35 injection. CONCLUSIONS: Seipin deficiency in astrocytes increases GSK3beta activity and levels of IL-6 and TNF-alpha through reducing PPARgamma, which can facilitate Abeta25-35/1-42-induced neuroinflammation to cause the death of neuronal cells and cognitive deficits. |
