Reducing the Levels of Akt Activation by PDK1 Knock-in Mutation Protects Neuronal Cultures against Synthetic Amyloid-Beta Peptides

Abstract

The Akt kinase has been widely assumed for years as a key downstream effector of the PI3K signaling pathway in promoting neuronal survival. This notion was however challenged by the finding that neuronal survival responses were still preserved in mice with reduced Akt activity. Moreover, here we show that the Akt signaling is elevated in the aged brain of two different mice models of Alzheimer Disease. We manipulate the rate of Akt stimulation by employing knock-in mice expressing a mutant form of PDK1 (phosphoinositide-dependent protein kinase 1) with reduced, but not abolished, ability to activate Akt. We found increased membrane localization and activity of the TACE/ADAM17 α-secretase in the brain of the PDK1 mutant mice with concomitant TNFR1 processing, which provided neurons with resistance against TNFα-induced neurotoxicity. Opposite to the Alzheimer Disease transgenic mice, the PDK1 knock-in mice exhibited an age-dependent attenuation of the unfolding protein response, which protected the mutant neurons against endoplasmic reticulum stressors. Moreover, these two mechanisms cooperatively provide the mutant neurons with resistance against amyloid-beta oligomers, and might singularly also contribute to protect these mice against amyloid-beta pathology.

uPAR Knockout Results in a Deep Glycolytic and OXPHOS Reprogramming in Melanoma and Colon Carcinoma Cell Lines

“…Moreover, we recently observed that uPAR drives a glycolytic phenotype in melanoma cells [25], triggering a Warburg phenotype mediated by the complex α5β1-integrin-uPAR-EGFR. By using siRNA targeting uPAR, we also previously demonstrated a downregulation of PDK1, which normally promotes the phosphorylation of Akt [36,37]. The inhibition of PDK1 not only inhibits the glycolytic profile of cancer cells, but its downregulation may also be responsible for the enhancement of the spare respiratory capacity observed in uPAR KO cancer cells.…”

Aging‐induced Akt activation involves in aging‐related pathologies and Aβ‐induced toxicity

“…The Akt (protein kinase B) signaling pathway is involved in both aging and AD. Aged brains were found to be associated with an imbalance of phosphatidylinositide 3‐kinases (PI3k)/Akt signaling (Jackson, Rani, Kumar, & Foster, ; Jiang, Yin, Yao, Brinton & Cadenas, ; Yang et al, ). In addition to the alteration of PI3K/Akt signaling in the aged brain, increased Akt phosphorylation is also observed in other aging tissues.…”

Production of seedable Amyloid-β peptides in model of prion diseases upon PrPSc-induced PDK1 overactivation

“…The accelerated death of prion-infected mice with Aβ deposition might be due to the occurrence of mixed pathologies, that are prion disease and CAA 11 . In any case, inhibiting PDK1 counteracts the toxicity of both prion and transmitted Aβ seeds as BX912 infusion in prion-infected APP23 mice not only reduces the load of PrP Sc , but also the brain deposition of Aβ, which thus reinforces the critical role of PDK1 in amyloid-based neurodegenerative diseases 23,24,57,58 .…”