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



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.



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.



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.
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.
Yun
Y
Qian
Department of Physiology, Nanjing Medical University, Hanzhong Road 140, Nanjing, 210029, China.
Jun
J
Yin
State Key Laboratory of Reproductive Medicine, Hanzhong Road 140, Nanjing, 210029, China.|Department of Physiology, Nanjing Medical University, Hanzhong Road 140, Nanjing, 210029, China.
Juan
J
Hong
State Key Laboratory of Reproductive Medicine, Hanzhong Road 140, Nanjing, 210029, China.|Department of Physiology, Nanjing Medical University, Hanzhong Road 140, Nanjing, 210029, China.
Guoxi
G
Li
Department of Physiology, Nanjing Medical University, Hanzhong Road 140, Nanjing, 210029, China.
Baofeng
B
Zhang
Institute of Cardiovascular Sciences, Peking University and Key Laboratory of Cardiovascular Sciences, China Administration of Education, Beijing, 100191, China.
George
G
Liu
Department of Neurology, First Affiliated Hospital of Nanjing Medical University, Guangzhou Road 300, Nanjing, 210029, China. qi_wan@126.com.
Qi
Q
Wan
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.
Ling
L
Chen
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D003072:Cognition Disorders / Q000209:etiology; D004195:Disease Models, Animal; D004660:Encephalitis / Q000209:etiology / Q000235:genetics / Q000473:pathology; D044388:GTP-Binding Protein gamma Subunits; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D020962:Heterotrimeric GTP-Binding Proteins / Q000172:deficiency* / Q000235:genetics; D006624:Hippocampus / Q000378:metabolism*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000378:metabolism; D020258:Neurotoxicity Syndromes / Q000209:etiology / Q000235:genetics / Q000473:pathology; D047495:PPAR gamma / Q000378:metabolism*; D010446:Peptide Fragments / Q000633:toxicity*
C491049:Aif1 protein, mouse; D016229:Amyloid beta-Peptides; C115783:Bscl2 protein, mouse; D002135:Calcium-Binding Proteins; D044388:GTP-Binding Protein gamma Subunits; D005904:Glial Fibrillary Acidic Protein; D008840:Microfilament Proteins; D047495:PPAR gamma; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); C074636:amyloid beta-protein (25-35); D000071679:Glycogen Synthase Kinase 3 beta; D020962:Heterotrimeric GTP-Binding Proteins
Glycogen synthase kinase-3 (GSK3); Neuroinflammation; Peroxisome proliferator-activated receptor gamma (PPARγ); Seipin; β-amyloid (Aβ)