PRAK mediates Aβ-RAGE driven autophagy pathway

Alzheimer’s disease (AD) is an irreversible progressive neurodegenerative disorder, resulting in loss of memory and behavioral changes. It is characterized by amyloid-β (Aβ) plaques, neurofibrillary tangles, and synaptic loss. Aβ affects AD pathogenesis, including oxidative stress, inflammatory response, and neuronal death. The intermediate mechanism between Aβ toxicity and AD pathogenesis is a subject of ongoing investigation. So far, there is no disease-modifying drug for AD and the available FDA-approved drugs are only useful for the symptomatic treatment of the patients [1]. The receptor for advanced glycation end products (RAGE), which has multi-ligands including AGE, S100, and Aβ, has recently attracted much attention for its involvement in various diseases such as type 2 diabetes, cardiovascular disease, and AD. Although RAGEmediated cellular signaling is reported in inflammation, apoptosis, cell migration, and autophagy [2], the lack of a signal transduction motif in the cytoplasmic domain of RAGE raises a question regarding the mechanism by which downstream signals are triggered inside the cell. We have recently shown that Aβ-RAGE interaction recruits p38-regulated/activated protein kinase (PRAK) to the RAGE cytoplasmic domain in vitro and in vivo. This direct binding between RAGE and PRAK has been confirmed by various biochemical tools such as yeast two hybrid (Y2H) screening, immunoprecipitation (IP), and surface plasmon resonance (SPR) assay [3]. PRAK is a member of the MAPKs and can be activated by phosphorylation in response to cellular stress and proinflammatory cytokines. It plays a critical role in cellular homeostasis such as angiogenesis, cell cycle, and neuronal plasticity. Moreover, PRAK regulates the phosphorylation of Ras homolog enriched in brain (Rheb), a key component of mammalian target of rapamycin complex 1 (mTORC1) [4]. When Aβ binds to the RAGE, PRAK is activated through its interaction with the RAGE cytoplasmic domain. Experimental evidence showed that unlike the full-length human RAGE overexpressing cells, PRAK is not phosphorylated by Aβ treatment in the cells expressing the cytoplasmic domain deletion mutant of RAGE (DNRAGE), suggesting that the cytoplasmic domain of RAGE is essential for the recruitment of PRAK upon Aβ binding to RAGE. To investigate the effect of Aβ on PRAK-RAGEmediated signaling pathway, we focused on the alteration of Rheb or mTORC1/p70S6k because PRAK is a kinase for Rheb in a cellular growth system [4]. Cells treated with Aβ showed increased levels of phosphorylated Rheb and p70S6k; however, these levels were not altered in the DN-RAGE-expressing or PRAK-silenced (siPRAK) cells. These data indicate that Rheb-mTORC1/p70S6k pathway is activated under Aβ stimulation and that it depends on the PRAK-RAGE interaction. Editorial