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Neuronal seipin knockout facilitates Aβ-induced neuroinflammation and neurotoxicity via reduction of PPARγ in hippocampus of mouse.
J Neuroinflammation. 2016 06 10; 13(1):145.JN

Abstract

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 Aβ25-35 (1.2 nmol/mouse) or Aβ1-42 (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 Aβ25-35/1-42 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 Aβ25-35/1-42 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 Aβ25-35/1-42-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 Aβ25-35 injection.

CONCLUSIONS

Seipin deficiency in astrocytes increases GSK3β activity and levels of IL-6 and TNF-α through reducing PPARγ, which can facilitate Aβ25-35/1-42-induced neuroinflammation to cause the death of neuronal cells and cognitive deficits.

Authors+Show Affiliations

State Key Laboratory of Reproductive Medicine, Hanzhong Road 140, Nanjing, 210029, China. Department of Neurology, First Affiliated Hospital of Nanjing Medical University, Guangzhou Road 300, Nanjing, 210029, China.Department of Physiology, Nanjing Medical University, Hanzhong Road 140, Nanjing, 210029, China.State Key Laboratory of Reproductive Medicine, Hanzhong Road 140, Nanjing, 210029, China. Department of Physiology, Nanjing Medical University, Hanzhong Road 140, Nanjing, 210029, China.State Key Laboratory of Reproductive Medicine, Hanzhong Road 140, Nanjing, 210029, China. Department of Physiology, Nanjing Medical University, Hanzhong Road 140, Nanjing, 210029, China.Department of Physiology, Nanjing Medical University, Hanzhong Road 140, Nanjing, 210029, China.Institute of Cardiovascular Sciences, Peking University and Key Laboratory of Cardiovascular Sciences, China Administration of Education, Beijing, 100191, China.Department of Neurology, First Affiliated Hospital of Nanjing Medical University, Guangzhou Road 300, Nanjing, 210029, China. qi_wan@126.com.State Key Laboratory of Reproductive Medicine, Hanzhong Road 140, Nanjing, 210029, China. lingchen@njmu.edu.cn. Department of Physiology, Nanjing Medical University, Hanzhong Road 140, Nanjing, 210029, China. lingchen@njmu.edu.cn.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27287266

Citation

Qian, Yun, et al. "Neuronal Seipin Knockout Facilitates Aβ-induced Neuroinflammation and Neurotoxicity Via Reduction of PPARγ in Hippocampus of Mouse." Journal of Neuroinflammation, vol. 13, no. 1, 2016, p. 145.
Qian Y, Yin J, Hong J, et al. Neuronal seipin knockout facilitates Aβ-induced neuroinflammation and neurotoxicity via reduction of PPARγ in hippocampus of mouse. J Neuroinflammation. 2016;13(1):145.
Qian, Y., Yin, J., Hong, J., Li, G., Zhang, B., Liu, G., Wan, Q., & Chen, L. (2016). Neuronal seipin knockout facilitates Aβ-induced neuroinflammation and neurotoxicity via reduction of PPARγ in hippocampus of mouse. Journal of Neuroinflammation, 13(1), 145. https://doi.org/10.1186/s12974-016-0598-3
Qian Y, et al. Neuronal Seipin Knockout Facilitates Aβ-induced Neuroinflammation and Neurotoxicity Via Reduction of PPARγ in Hippocampus of Mouse. J Neuroinflammation. 2016 06 10;13(1):145. PubMed PMID: 27287266.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Neuronal seipin knockout facilitates Aβ-induced neuroinflammation and neurotoxicity via reduction of PPARγ in hippocampus of mouse. AU - Qian,Yun, AU - Yin,Jun, AU - Hong,Juan, AU - Li,Guoxi, AU - Zhang,Baofeng, AU - Liu,George, AU - Wan,Qi, AU - Chen,Ling, Y1 - 2016/06/10/ PY - 2016/01/27/received PY - 2016/05/24/accepted PY - 2016/6/12/entrez PY - 2016/6/12/pubmed PY - 2017/10/11/medline KW - Glycogen synthase kinase-3 (GSK3) KW - Neuroinflammation KW - Peroxisome proliferator-activated receptor gamma (PPARγ) KW - Seipin KW - β-amyloid (Aβ) SP - 145 EP - 145 JF - Journal of neuroinflammation JO - J Neuroinflammation VL - 13 IS - 1 N2 - 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 Aβ25-35 (1.2 nmol/mouse) or Aβ1-42 (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 Aβ25-35/1-42 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 Aβ25-35/1-42 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 Aβ25-35/1-42-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 Aβ25-35 injection. CONCLUSIONS: Seipin deficiency in astrocytes increases GSK3β activity and levels of IL-6 and TNF-α through reducing PPARγ, which can facilitate Aβ25-35/1-42-induced neuroinflammation to cause the death of neuronal cells and cognitive deficits. SN - 1742-2094 UR - https://www.unboundmedicine.com/medline/citation/27287266/Neuronal_seipin_knockout_facilitates_Aβ_induced_neuroinflammation_and_neurotoxicity_via_reduction_of_PPARγ_in_hippocampus_of_mouse_ L2 - https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-016-0598-3 DB - PRIME DP - Unbound Medicine ER -