| First Author | Chang H | Year | 2019 |
| Journal | Neurobiol Dis | Volume | 127 |
| Pages | 350-361 | PubMed ID | 30910747 |
| Mgi Jnum | J:278137 | Mgi Id | MGI:6355900 |
| Doi | 10.1016/j.nbd.2019.03.023 | Citation | Chang H, et al. (2019) Seipin deletion in mice enhances phosphorylation and aggregation of tau protein through reduced neuronal PPARgamma and insulin resistance. Neurobiol Dis 127:350-361 |
| abstractText | Congenital generalized lipodystrophy 2 (CGL2) is characterized by loss of adipose tissue, insulin resistance and cognitive deficits and caused by mutation of BSCL2/seipin gene. Seipin deletion in mice and rats causes severe lipodystrophy, insulin resistance, and cognitive impairment. Hippocampal neurons express seipin protein. This study aimed to investigate the influence of systemic seipin knockout (seipin-sKO), neuronal seipin knockout (seipin-nKO) or adipose seipin knockout (seipin-aKO) in hippocampal tau phosphorylation and aggregation. Levels of tau phosphorylation at Thr(212)/Ser(214) and Ser(202)/Thr(205) and oligomer tau protein were increased in seipin-sKO mice and seipin-nKO mice with a decrease in axonal density and expression of PPARgamma. Neuronal seipin deletion increased activities of GSK3beta and Akt/mTOR signaling, which were corrected by the administration of PPARgamma agonist rosiglitazone for 7days. The autophagosome formation was reduced in seipin-sKO mice and seipin-nKO mice, which was rescued by the Akt and mTOR inhibitors. The administration of rosiglitazone or Akt, mTOR and GSK3beta inhibitors for 7days could correct the hyperphosphorylation and aggregation of tau. On the other hand, seipin-sKO mice appeared insulin resistance and an increase in phosphorylation of tau at Ser(396) and JNK, which were corrected by treatment with rosiglitazone for 30days rather than 7days. Inhibition of JNK in seipin-sKO mice corrected the hyperphosphorylated tau at Ser(396). The results indicate that neuronal seipin deletion causes hyperphosphorylation and aggregation of tau protein leading to axonal atrophy through reduced PPARgamma to enhance GSK3beta and Akt/mTOR signaling; systemic seipin deletion-induced insulin resistance causes tau hyperphosphorylation via cascading JNK pathway. |
