Role of inorganic polyphosphates in the activation of AMPK in models of Alzheimer's disease.

Abstract

Inorganic polyphosphate (polyP) is composed of multiple phosphates linked together by phosphoanhydride bonds, similar to those found in ATP. PolyP shows a high colocalization with mammalian mitochondria and it acts as an energy buffer in different organisms. In mammals, polyP regulates cellular bioenergetics, via a mechanism which is not yet understood. Lack of mitochondrial polyP induces a mitochondrial dysfunction, including bioenergetics, similar to what is found in some neurodegenerative diseases, such as Alzheimer's disease (AD). One plausible mechanism explaining this dysfunction could involve the regulation of the AMP-activated protein kinase (AMPK), a main energy gauge in mammalian cells, by polyP. To study the effects of polyP on mitochondrial physiology and whether these effects are mediated by polyP's regulation of the AMPK, we used two models of AD: i) human fibroblasts from healthy individuals and from AD patients, and ii) SH-SY5Y cells under control and treated with Aβ42. In both models, we used Wild-type (Wt) and enzymatically depleted of mitochondrial polyP (MitoPPX) cells. Our data show that Aβ42 affects MitoPPX cells differently compared to Wt cells. Moreover, we assessed polyP levels in our fibroblasts and observed different levels in our AD fibroblasts, compared to our healthy individual fibroblasts. Additionally, we also show that the activation of AMPK is affected by the enzymatic depletion of mitochondrial polyP in our models. Our data suggest an important role for polyP in cellular bioenergetics, via the regulation of AMPK. Our studies could pave the road to find therapeutic strategies to reverse or slow down the symptoms of AD.