Activated mTOR and PKR Kinases in Lymphocytes Correlate with Memory and Cognitive Decline in Alzheimer’s Disease

Pocard, Marc; Pain, Stéphanie; Pluchon, Claudette; Paul, Chloé; Besson, Marie-Noelle; Carret-Rebillat, Anne-Sophie; Bilan, Agnès Rioux; Gil, Roger; Hugon, Jacques

doi:10.1159/000095562

Cited by 86 publications

(64 citation statements)

References 52 publications

(37 reference statements)

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“…Expression of cytosolic PrP C has also been shown to activate PKR (39), and neuronal immunostaining for activated PKR has been found in cases of Creuztfeldt-Jakob disease (40). Interestingly, phosphorylated PKR is also a marker for cognitive decline in individuals with Alzheimer's disease (41) and, in cultured neurons, PKR activation and eIF2α phosphorylation play a role in the induction of apoptosis by β-amyloid peptides (42).…”

Section: Discussionmentioning

confidence: 99%

Prion protein interaction with stress-inducible protein 1 enhances neuronal protein synthesis via mTOR

Roffé

Beraldo

Bester

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Section: Discussionmentioning

confidence: 99%

Prion protein interaction with stress-inducible protein 1 enhances neuronal protein synthesis via mTOR

Roffé

Beraldo

Bester

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…We also found that activation of PKR and eIF2 ␣ is crucial in ␤ -amyloid (A ␤ )-induced apoptosis in cultured cortical neurons [38] , where extracellular accumulation of A ␤ peptides is a key pathological hallmark of AD [39] . In a recent study, the levels of phospho-PKR and phospho-eIF2 ␣ have been found to be elevated in lymphocytes of AD patients, and these changes were significantly correlated with the cognitive and memory test scores [40] .…”

Section: Pkr and Neurodegenerative Diseasesmentioning

confidence: 94%

Significance of Molecular Signaling for Protein Translation Control in Neurodegenerative Diseases

Chang

Lai

2006

Neurosignals

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It has long been known that protein synthesis is inhibited in neurological disorders. Protein synthesis includes protein transcription and translation. While many studies about protein transcription have been done in the last decade, we are just starting to understand more about the impact of protein translation. Protein translation control can be accomplished at the initiation or elongation steps. In this review, we will focus on translation control at initiation. Neurons have long neurites in which proteins have to be transported from the cell body to the end of the neurite. Since supply of proteins cannot meet the need of neuronal activity at the spine, protein locally translated at the spine will be a good solution to replace the turnover of proteins. Therefore, local protein translation is an important mechanism to maintain normal neuronal functions. In this notion, we have to separate the concept of global and local protein translation control. Both global and local protein translation control modulate normal neuronal functions from development to cognitive functions. Increasing lines of evidence show that they also play significant roles in neurodegenerative diseases, e.g. neuronal apoptosis, synaptic degeneration and autophagy. We summarize all the evidence in this review and focus on the control at initiation. The new live-cell imaging technology together with photoconvertible fluorescent probes allows us to investigate newly translated proteins in situ. Protein translation control is another line to modulate neuronal function in neuron-neuron communication as well as in response to stress in neurodegenerative diseases.

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“…Loss of mTOR impairs the reconsolidation phase of traumatic memory (98). In patients with AD, a decrease in mTOR activity in peripheral lymphocytes appears to correlate with the progression of AD (99). Loss of mTOR signaling also has been shown to impair long-term potentiation and synaptic plasticity in animal models of AD that can be restored through the upregulation of mTOR signaling (100).…”

Section: Mtor In Memory and Alzheimer’s Diseasementioning

confidence: 99%

Taking aim at Alzheimer's disease through the mammalian target of rapamycin

Maiese¹

2014

Annals of Medicine

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A significant portion of the world’s population suffers from sporadic Alzheimer’s disease (AD) with available present therapies limited to symptomatic care that does not alter disease progression. Over the next decade, advancing age of the global population will dramatically increase the incidence of AD and severely impact health care resources, necessitating novel, safe, and efficacious strategies for AD. The mammalian target of rapamycin (mTOR) and its protein complexes mTOR Complex 1 (mTORC1) and mTOR Complex 2 (mTORC2) offer exciting and unique avenues of intervention for AD through the oversight of programmed cell death pathways of apoptosis, autophagy, and necroptosis. mTOR modulates multi-faceted signal transduction pathways that involve phosphoinositide 3-kinase (PI 3-K), protein kinase B (Akt), hamartin (tuberous sclerosis 1)/tuberin (tuberous sclerosis 2) (TSC1/TSC2) complex, proline-rich Akt substrate 40 kDa (PRAS40), and p70 ribosomal S6 kinase (p70S6K) and can interface with the neuroprotective pathways of growth factors, sirtuins, wingless, fork-head transcription factors, and glycogen synthase kinase-3β. With the ability of mTOR to broadly impact cellular function, clinical strategies for AD that implement mTOR must achieve parallel objectives of protecting neuronal, vascular, and immune cell survival in conjunction with preserving networks that determine memory and cognitive function.

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Activated mTOR and PKR Kinases in Lymphocytes Correlate with Memory and Cognitive Decline in Alzheimer’s Disease

Cited by 86 publications

References 52 publications

Prion protein interaction with stress-inducible protein 1 enhances neuronal protein synthesis via mTOR

Prion protein interaction with stress-inducible protein 1 enhances neuronal protein synthesis via mTOR

Significance of Molecular Signaling for Protein Translation Control in Neurodegenerative Diseases

Taking aim at Alzheimer's disease through the mammalian target of rapamycin

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