Aβ inhibits SREBP-2 activation through Akt inhibition

We previously demonstrated that oligomeric amyloid β₄₂ (oAβ₄₂) 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 oAβ₄₂, 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 oAβ₄₂ 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. oAβ₄₂ 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 oAβ₄₂ on SREBP-2 and the downstream inhibition of cholesterol synthesis and protein prenylation. Our work provides a novel mechanistic link between Aβ 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.