| First Author | Mohamed A | Year | 2018 |
| Journal | J Lipid Res | Volume | 59 |
| Issue | 1 | Pages | 1-13 |
| PubMed ID | 29122977 | Mgi Jnum | J:256420 |
| Mgi Id | MGI:6108081 | Doi | 10.1194/jlr.M076703 |
| Citation | Mohamed A, et al. (2018) Abeta inhibits SREBP-2 activation through Akt inhibition. J Lipid Res 59(1):1-13 |
| abstractText | We previously demonstrated that oligomeric amyloid beta42 (oAbeta42) inhibits the mevalonate pathway impairing cholesterol synthesis and protein prenylation. Enzymes of the mevalonate pathway are regulated by the transcription factor SREBP-2. Here, we show that in several neuronal types challenged with oAbeta42, SREBP-2 activation is reduced. Moreover, SREBP-2 activation is also decreased in the brain cortex of the Alzheimer''s disease (AD) mouse model, TgCRND8, suggesting that SREBP-2 may be affected in vivo early in the disease. We demonstrate that oAbeta42 does not affect enzymatic cleavage of SREBP-2 per se, but may impair SREBP-2 transport from the endoplasmic reticulum (ER) to the Golgi. Trafficking of SREBP-2 from the ER to the Golgi requires protein kinase B (Akt) activation. oAbeta42 significantly reduces Akt phosphorylation and this decrease is responsible for the decline in SREBP-2 activation. Overexpression of constitutively active Akt prevents the effect of oAbeta42 on SREBP-2 and the downstream inhibition of cholesterol synthesis and protein prenylation. Our work provides a novel mechanistic link between Abeta and the mevalonate pathway, which will impact the views on issues related to cholesterol, isoprenoids, and statins in AD. We also identify SREBP-2 as an indirect target of Akt in neurons, which may play a role in the cross-talk between AD and diabetes. |
