Mechanisms sustaining deregulation of the PDK1/TACE signaling axis by amyloid proteins: from pathological implications to therapeutic interventions for prion and Alzheimer’s diseases. – TargetingPDK1inAD

Alzheimer’s disease (AD) is the most common dementia in human and concerns 35 million individuals worldwide. As the population ages and because of the impossibility to diagnose with accuracy the pathology at early stages, there is a pressing need to develop new therapies to attenuate memory impairments. A better understanding of AD physiopathology is a prerequisite to design potent therapies to treat this neurodegenerative disorder. Our recent work on prion diseases (e.g. Creutzfeldt-Jakob disease) and AD revealed common neurodegenerative mechanisms and identified the kinase PDK1 as a potential therapeutic target for both diseases (Nat. Med., 2013). Pathogenic PrPSc found in prion diseases and neurotoxic amyloid Aß peptides in AD provoke overactivation of PDK1 in diseased neurons. Overactivated PDK1 triggers in turn the phosphorylation and internalization of the a-secretase TACE (TNFa Converting Enzyme, ADAM17) in caveolin-1-enriched vesicles, which cancels its cell surface neuroprotective function (Nat. Med., 2013; Plos Pathogens, 2015). Notably, PDK1-dependent TACE internalization diverts TACE cleavage activity away from three main substrates (i) the normal cellular prion protein, PrPC, i.e. the non-pathological isoform of PrPSc, which favors the conversion of PrPC into PrPSc in prion diseases, (ii) the amyloid precursor protein, which amplifies the production of Aß peptides in AD, and (iii) TNFa receptors, which render prion-infected and AD neurons highly sensitive to TNFa toxicity. Antagonizing PDK1 activity allows to redirect TACE to the plasma membrane and to rescue its cleavage activity, which attenuates PrPSc- and Aß-associated neurotoxicities. In mice, the pharmacological inhibition of PDK1 mitigates both prion diseases and AD with decrease in brain PrPSc and Aß levels and reduction of behavioral, memory and cognitive deficits. The therapeutic relevance of our data is supported by an elevated PDK1 activity and reduced TACE cleavage activity in the brain of AD individuals. However, available PDK1 inhibitors are toxic per se, which limits their immediate use for treating prion and Alzheimer’s diseases in humans, and therefore calls for a better knowledge of the biochemical mechanisms sustaining deregulation of the PDK1/TACE signaling module along prion and Alzheimer’s neuropathogeneses. Combining in vitro and in vivo approaches, this proposal aims at investigating at the cellular and molecular levels the mechanisms causing PDK1 overactivation in prion-infected and “Alzheimer’s” neurons and TACE internalization in a PDK1-dependent manner. Our goal is also to identify through global approaches the set of proteins co-internalized with TACE in caveolin-1-enriched vesicles since changes in their cell localization may affect their activity and contribute to neurodegeneration. Whether PDK1 overactivation promotes neurodegeneration in AD through dysfunction of the microtubule-associated protein Tau will be investigated. Finally, the stake of this project is to assess the occurrence of such mechanisms revealed in vitro with the help of neuronal cultures in vivo in mouse models with human sporadic Creutzfeldt-Jakob disease (sCJD) or Alzheimer’s disease as well as in samples from sCJD and AD individuals. This study will thus provide new insights into AD and prion physiopathologies and help to design new therapeutic strategies connected to PDK1 signaling to combat these two neurodegenerative diseases, for which no efficient medicine are proposed so far.