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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 (PPARγ) level without the loss of pyramidal cells. The down-regulation of PPARγ has gained increasing attention in neuroinflammation of Alzheimer’s disease (AD). Thus, the present study focused on exploring the influence of seipin depletion on β-amyloid (Aβ)-induced neuroinflammation and Aβ neurotoxicity.    Methods  Adult male  seipin -KO mice were treated with a single intracerebroventricular (i.c.v.) injection of Aβ 25–35  (1.2 nmol/mouse) or Aβ 1–42  (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 Aβ 25–35/1–42  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-α were slightly increased. Similarly, the Aβ 25–35/1–42  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-α. Treatment of the  seipin -KO mice with the PPARγ agonist rosiglitazone (rosi) could prevent Aβ 25–35/1–42 -induced neuroinflammation and neurotoxicity, which was blocked by the PPARγ antagonist GW9962. In the  seipin -KO mice, the level of glycogen synthase kinase-3β (GSK3β) 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 Aβ 25–35  injection.    Conclusions  Seipin deficiency in astrocytes increases GSK3β activity and levels of IL-6 and TNF-α through reducing PPARγ, which can facilitate Aβ 25–35/1–42 -induced neuroinflammation to cause the death of neuronal cells and cognitive deficits.    Electronic supplementary material  The online version of this article (doi:10.1186/s12974-016-0598-3) contains supplementary material, which is available to authorized users.

Neuronal seipin knockout facilitates Aβ-induced neuroinflammation and neurotoxicity via reduction of PPARγ in hippocampus of mouse