scholarly journals Investigation of the Biological Effect of eIF4A Reduction and Inhibition

2021 ◽  
Author(s):  
◽  
Richard Little
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Translation Initiation ◽  
Ribosome Biogenesis ◽  
Viral Infections ◽  
Human Cells ◽  
Telomere Maintenance ◽  
Initiation Factor ◽  
Current Evidence ◽  
Multiple Drugs

<p>Translation initiation has been identified as a therapeutic target for many diseases including cancers, Alzheimer’s disease, viral infections and cachexia. One protein involved in this process is the eukaryotic initiation factor 4A (eIF4A), an RNA helicase that is integral for cap-dependent translation initiation. Multiple drugs that inhibit the normal function of eIF4A have been identified, with one currently entering clinical trials. Recent investigations into the effects of eIF4A inhibitor treatment, however, have used concentrations that significantly hinder cell proliferation and survival. However, applications in Alzheimer’s disease, viral infections and cachexia require much lower inhibitor concentrations. Current evidence shows that under these conditions, inhibition of eIF4A leads to disruption of translation of individual transcripts in a manner that is dependent on their sequence and structure. However, the cell-wide effects of eIF4A inhibition at these low concentrations is still not known, and so the mechanisms through which treatments for these diseases will function are not fully elucidated.  Using an expression-based analysis, we investigated the effects of mild perturbation of eIF4A through gene deletion mutations in yeast and low doses of the eIF4A inhibitor pateamine on human cells. With both these approaches we identify a range of expression changes in proteins throughout the proteostatic network, relating to processes such as translation, amino acid production, ribosome biogenesis, protein folding and protein degradation. Processes further removed from translation initiation were also found to be affected but differed between yeast and human cell line models, with energy metabolism being affected in yeast, and telomere maintenance and mRNA metabolism being affected in human cells. We also identified an mRNA 5′ untranslated region sequence that appears to confer a disproportionate reduction in expression only seen in pateamine treatment conditions. Through this approach we identify the key cellular effects of altered eIF4A function and demonstrate differences between reduced eIF4A function and pateamine inhibition.</p>

scholarly journals Investigation of the Biological Effect of eIF4A Reduction and Inhibition

2021 ◽  
Author(s):  
◽  
Richard Little
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Translation Initiation ◽  
Ribosome Biogenesis ◽  
Viral Infections ◽  
Human Cells ◽  
Telomere Maintenance ◽  
Initiation Factor ◽  
Current Evidence ◽  
Multiple Drugs

<p>Translation initiation has been identified as a therapeutic target for many diseases including cancers, Alzheimer’s disease, viral infections and cachexia. One protein involved in this process is the eukaryotic initiation factor 4A (eIF4A), an RNA helicase that is integral for cap-dependent translation initiation. Multiple drugs that inhibit the normal function of eIF4A have been identified, with one currently entering clinical trials. Recent investigations into the effects of eIF4A inhibitor treatment, however, have used concentrations that significantly hinder cell proliferation and survival. However, applications in Alzheimer’s disease, viral infections and cachexia require much lower inhibitor concentrations. Current evidence shows that under these conditions, inhibition of eIF4A leads to disruption of translation of individual transcripts in a manner that is dependent on their sequence and structure. However, the cell-wide effects of eIF4A inhibition at these low concentrations is still not known, and so the mechanisms through which treatments for these diseases will function are not fully elucidated.  Using an expression-based analysis, we investigated the effects of mild perturbation of eIF4A through gene deletion mutations in yeast and low doses of the eIF4A inhibitor pateamine on human cells. With both these approaches we identify a range of expression changes in proteins throughout the proteostatic network, relating to processes such as translation, amino acid production, ribosome biogenesis, protein folding and protein degradation. Processes further removed from translation initiation were also found to be affected but differed between yeast and human cell line models, with energy metabolism being affected in yeast, and telomere maintenance and mRNA metabolism being affected in human cells. We also identified an mRNA 5′ untranslated region sequence that appears to confer a disproportionate reduction in expression only seen in pateamine treatment conditions. Through this approach we identify the key cellular effects of altered eIF4A function and demonstrate differences between reduced eIF4A function and pateamine inhibition.</p>

scholarly journals Correction of eIF2-dependent defects in brain protein synthesis, synaptic plasticity, and memory in mouse models of Alzheimer’s disease

2021 ◽  
Vol 14 (668) ◽  
pp. eabc5429
Author(s):  
Mauricio M. Oliveira ◽  
Mychael V. Lourenco ◽  
Francesco Longo ◽  
Nicole P. Kasica ◽  
Wenzhong Yang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Synthesis ◽  
Synaptic Plasticity ◽  
Translation Initiation ◽  
Mrna Translation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Postmortem Brain Tissue ◽  
Phosphorylated Eif2α

Neuronal protein synthesis is essential for long-term memory consolidation, and its dysregulation is implicated in various neurodegenerative disorders, including Alzheimer’s disease (AD). Cellular stress triggers the activation of protein kinases that converge on the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α), which attenuates mRNA translation. This translational inhibition is one aspect of the integrated stress response (ISR). We found that postmortem brain tissue from AD patients showed increased phosphorylation of eIF2α and reduced abundance of eIF2B, another key component of the translation initiation complex. Systemic administration of the small-molecule compound ISRIB (which blocks the ISR downstream of phosphorylated eIF2α) rescued protein synthesis in the hippocampus, measures of synaptic plasticity, and performance on memory-associated behavior tests in wild-type mice cotreated with salubrinal (which inhibits translation by inducing eIF2α phosphorylation) and in both β-amyloid-treated and transgenic AD model mice. Thus, attenuating the ISR downstream of phosphorylated eIF2α may restore hippocampal protein synthesis and delay cognitive decline in AD patients.

scholarly journals Correction of eIF2-dependent defects in brain protein synthesis, synaptic plasticity and memory in mouse models of Alzheimer’s disease

2020 ◽  
Author(s):  
Mauricio M. Oliveira ◽  
Mychael V. Lourenco ◽  
Francesco Longo ◽  
Nicole P. Kasica ◽  
Wenzhong Yang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Synthesis ◽  
Synaptic Plasticity ◽  
Mouse Models ◽  
Translation Initiation ◽  
Mrna Translation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Long Term Memory

AbstractNeuronal protein synthesis is essential for long-term memory consolidation. Conversely, dysregulation of protein synthesis has been implicated in a number of neurodegenerative disorders, including Alzheimer’s disease (AD). Several types of cellular stress trigger the activation of protein kinases that converge on the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α-P). This leads to attenuation of cap-dependent mRNA translation, a component of the integrated stress response (ISR). We show that AD brains exhibit increased eIF2α-P and reduced eIF2B, key components of the eIF2 translation initiation complex. We further demonstrate that attenuating the ISR with the small molecule compound ISRIB (ISR Inhibitor) rescues hippocampal protein synthesis and corrects impaired synaptic plasticity and memory in mouse models of AD. Our findings suggest that attenuating eIF2α-P-mediated translational inhibition may comprise an effective approach to alleviate cognitive decline in AD.

Integrated Biomarkers for Depression in Alzheimer’s Disease: A Critical Review

2017 ◽  
Vol 14 (4) ◽  
pp. 441-452 ◽  
Author(s):  
Sofia Wenzler ◽  
Christian Knochel ◽  
Ceylan Balaban ◽  
Dominik Kraft ◽  
Juliane Kopf ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Affect Regulation ◽  
Current Evidence ◽  
Diagnostic Process ◽  
Neuropsychiatric Manifestation ◽  
The Brain ◽  
Control Functional

Depression is a common neuropsychiatric manifestation among Alzheimer’s disease (AD) patients. It may compromise everyday activities and lead to a faster cognitive decline as well as worse quality of life. The identification of promising biomarkers may therefore help to timely initiate and improve the treatment of preclinical and clinical states of AD, and to improve the long-term functional outcome. In this narrative review, we report studies that investigated biomarkers for AD-related depression. Genetic findings state AD-related depression as a rather complex, multifactorial trait with relevant environmental and inherited contributors. However, one specific set of genes, the brain derived neurotrophic factor (BDNF), specifically the Val66Met polymorphism, may play a crucial role in AD-related depression. Regarding neuroimaging markers, the most promising findings reveal structural impairments in the cortico-subcortical networks that are related to affect regulation and reward / aversion control. Functional imaging studies reveal abnormalities in predominantly frontal and temporal regions. Furthermore, CSF based biomarkers are seen as potentially promising for the diagnostic process showing abnormalities in metabolic pathways that contribute to AD-related depression. However, there is a need for standardization of methodological issues and for replication of current evidence with larger cohorts and prospective studies.

scholarly journals Casein Kinase 2 dependent phosphorylation of eIF4B regulates BACE1 expression in Alzheimer’s disease

2021 ◽  
Vol 12 (8) ◽  
Author(s):  
Barbara Bettegazzi ◽  
Laura Sebastian Monasor ◽  
Serena Bellani ◽  
Franca Codazzi ◽  
Lisa Michelle Restelli ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neuronal Activity ◽  
Neurodegenerative Disorder ◽  
Brain Slices ◽  
Casein Kinase ◽  
Casein Kinase 2 ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Bace1 Expression

AbstractAlzheimer’s disease (AD) is the most common age-related neurodegenerative disorder. Increased Aβ production plays a fundamental role in the pathogenesis of the disease and BACE1, the protease that triggers the amyloidogenic processing of APP, is a key protein and a pharmacological target in AD. Changes in neuronal activity have been linked to BACE1 expression and Aβ generation, but the underlying mechanisms are still unclear. We provide clear evidence for the role of Casein Kinase 2 in the control of activity-driven BACE1 expression in cultured primary neurons, organotypic brain slices, and murine AD models. More specifically, we demonstrate that neuronal activity promotes Casein Kinase 2 dependent phosphorylation of the translation initiation factor eIF4B and this, in turn, controls BACE1 expression and APP processing. Finally, we show that eIF4B expression and phosphorylation are increased in the brain of APPPS1 and APP-KI mice, as well as in AD patients. Overall, we provide a definition of a mechanism linking brain activity with amyloid production and deposition, opening new perspectives from the therapeutic standpoint.

scholarly journals Proteins and microRNAs are differentially expressed in tear fluid from patients with Alzheimer’s disease

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Aidan Kenny ◽  
Eva M. Jiménez-Mateos ◽  
María Ascensión Zea-Sevilla ◽  
Alberto Rábano ◽  
Pablo Gili-Manzanaro ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Unmet Need ◽  
Cost Effective ◽  
Specific Protein ◽  
Tear Fluid ◽  
Initiation Factor ◽  
Non Invasive ◽  
A Genome ◽  
Potential Biomarker

Abstract Alzheimer’s disease (AD) is characterized by a progressive loss of neurons and cognitive functions. Therefore, early diagnosis of AD is critical. The development of practical and non-invasive diagnostic tests for AD remains, however, an unmet need. In the present proof-of-concept study we investigated tear fluid as a novel source of disease-specific protein and microRNA-based biomarkers for AD development using samples from patients with mild cognitive impairment (MCI) and AD. Tear protein content was evaluated via liquid chromatography-mass spectrometry and microRNA content was profiled using a genome-wide high-throughput PCR-based platform. These complementary approaches identified enrichment of specific proteins and microRNAs in tear fluid of AD patients. In particular, we identified elongation initiation factor 4E (eIF4E) as a unique protein present only in AD samples. Total microRNA abundance was found to be higher in tears from AD patients. Among individual microRNAs, microRNA-200b-5p was identified as a potential biomarker for AD with elevated levels present in AD tear fluid samples compared to controls. Our study suggests that tears may be a useful novel source of biomarkers for AD and that the identification and verification of biomarkers within tears may allow for the development of a non-invasive and cost-effective diagnostic test for AD.

scholarly journals Cerebrospinal Fluid Biomarkers of Alzheimer’s Disease: Current Evidence and Future Perspectives

2021 ◽  
Vol 11 (2) ◽  
pp. 215
Author(s):  
Donovan A. McGrowder ◽  
Fabian Miller ◽  
Kurt Vaz ◽  
Chukwuemeka Nwokocha ◽  
Cameil Wilson-Clarke ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Late Onset ◽  
Amyloid Β ◽  
Current Evidence ◽  
Csf Biomarkers ◽  
Diagnostic Efficacy ◽  
Neurofilament Light ◽  
New Biomarkers

Alzheimer’s disease is a progressive, clinically heterogeneous, and particularly complex neurodegenerative disease characterized by a decline in cognition. Over the last two decades, there has been significant growth in the investigation of cerebrospinal fluid (CSF) biomarkers for Alzheimer’s disease. This review presents current evidence from many clinical neurochemical studies, with findings that attest to the efficacy of existing core CSF biomarkers such as total tau, phosphorylated tau, and amyloid-β (Aβ42), which diagnose Alzheimer’s disease in the early and dementia stages of the disorder. The heterogeneity of the pathophysiology of the late-onset disease warrants the growth of the Alzheimer’s disease CSF biomarker toolbox; more biomarkers showing other aspects of the disease mechanism are needed. This review focuses on new biomarkers that track Alzheimer’s disease pathology, such as those that assess neuronal injury (VILIP-1 and neurofilament light), neuroinflammation (sTREM2, YKL-40, osteopontin, GFAP, progranulin, and MCP-1), synaptic dysfunction (SNAP-25 and GAP-43), vascular dysregulation (hFABP), as well as CSF α-synuclein levels and TDP-43 pathology. Some of these biomarkers are promising candidates as they are specific and predict future rates of cognitive decline. Findings from the combinations of subclasses of new Alzheimer’s disease biomarkers that improve their diagnostic efficacy in detecting associated pathological changes are also presented.

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