| First Author | Sajan MP | Year | 2018 |
| Journal | Neurobiol Aging | Volume | 61 |
| Pages | 225-237 | PubMed ID | 29032894 |
| Mgi Jnum | J:258056 | Mgi Id | MGI:6116560 |
| Doi | 10.1016/j.neurobiolaging.2017.09.001 | Citation | Sajan MP, et al. (2018) Atypical PKC, PKClambda/iota, activates beta-secretase and increases Abeta1-40/42 and phospho-tau in mouse brain and isolated neuronal cells, and may link hyperinsulinemia and other aPKC activators to development of pathological and memory abnormalities in Alzheimer's disease. Neurobiol Aging 61:225-237 |
| abstractText | Hyperinsulinemia activates brain Akt and PKC-lambda/iota and increases Abeta1-40/42 and phospho-tau in insulin-resistant animals. Here, we examined underlying mechanisms in mice, neuronal cells, and mouse hippocampal slices. Like Abeta1-40/42, beta-secretase activity was increased in insulin-resistant mice and monkeys. In insulin-resistant mice, inhibition of hepatic PKC-lambda/iota sufficient to correct hepatic abnormalities and hyperinsulinemia simultaneously reversed increases in Akt, atypical protein kinase C (aPKC), beta-secretase, and Abeta1-40/42, and restored acute Akt activation. However, 2 aPKC inhibitors additionally blocked insulin''s ability to activate brain PKC-lambda/iota and thereby increase beta-secretase and Abeta1-40/42. Furthermore, direct blockade of brain aPKC simultaneously corrected an impairment in novel object recognition in high-fat-fed insulin-resistant mice. In neuronal cells and/or mouse hippocampal slices, PKC-iota/lambda activation by insulin, metformin, or expression of constitutive PKC-iota provoked increases in beta-secretase, Abeta1-40/42, and phospho-thr-231-tau that were blocked by various PKC-lambda/iota inhibitors, but not by an Akt inhibitor. PKC-lambda/iota provokes increases in brain beta-secretase, Abeta1-40/42, and phospho-thr-231-tau. Excessive signaling via PKC-lambda/iota may link hyperinsulinemia and other PKC-lambda/iota activators to pathological and functional abnormalities in Alzheimer''s disease. |
