Dataset Information

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 ?-secretase in the brain of the PDK1 mutant mice with concomitant TNFR1 processing, which provided neurons with resistance against TNF?-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.

SUBMITTER: Yang S

PROVIDER: S-EPMC5766684 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Publications

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

Yang Shaobin S Pascual-Guiral Sònia S Ponce Rebeca R Giménez-Llort Lydia L Baltrons María A MA Arancio Ottavio O Palacio Jose R JR Clos Victoria M VM Yuste Victor J VJ Bayascas Jose R JR

Frontiers in aging neuroscience 20180108

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 ...[more]

PMID: 29358916

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Project description:Dysfunction and dysregulation at the genetic, neural, and behavioral levels point at the fine-tuning of broadly spread networks as critical for a wide array of behaviors and mental processes through the life span. This brain-based evidence, from basic to behavioral neuroscience levels, is leading to a new conceptualization of mental health and disease. Thus, the Research Domain Criteria considers phenotypic differences observed among disorders as explained by variations in the nature and degree of neural circuitry disruptions, under the modulation of several developmental, compensatory, environmental, and epigenetic factors. In this context, we aimed to describe for the first time the in vivo behavioral impact of tweaking the PI3K/Akt signaling pathway known to play an essential role in the regulation of cellular processes, leading to diverse physiological responses. We explored the effects in young (YA, 3-4 months of age) and mature (MA, 11-14 months of age) male and female PDK1 K465E knock-in mice in a battery of tests under different anxiogenic conditions. The results evidenced that the double mutation of the PDK1 pleckstrin homology (PH) domain resulted in an enhancement of the negative valence system shown as an increase of responses of fear- and anxiety-like behaviors in anxiogenic situations. Interestingly, this seemed to be specific of YA and found regulated at middle age. In contrast, cognitive deficits, as measured in a spatial working memory task, were found in both YA and MA mutants and independently of the level of their anxious-like profiles. These distinct age- and function-dependent impacts would be in agreement with the distinct cortical and limbic deficits in the Akt signaling in the brain we have recently described in these same animals. The elicitation of age- and neuronal-dependent specific patterns suggests that fine-tuning the intensity of the PKB/Akt signal that enables diverse physiological response has also its in vivo translation into the negative valence system and age is a key regulatory factor.

Dataset Information

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

Publications

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

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