ArticleNeuron2008
Phosphorylation of the translation initiation factor eIF2alpha increases BACE1 levels and promotes amyloidogenesis.
Article in Neuron, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 246 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
246 citing papers in PubMed, 1 synthesis or guideline pooled it, 416 citations in OpenAlex.
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- Alzheimer's Disease as a Multi-Layer Network Disorder: A Systems Biology Framework Integrating Multi-Omics Mechanisms.Biomedicines · 2026Review
- Allosteric disordering of eIF2B regulates the integrated stress response.Nature chemical biology · 2026Article
- The Effects of Coenzyme Q10 Supplementation on the Contrast Sensitivity Score, Biomarkers of Oxidative Stress, Inflammation, and β-Secretase Activity in the Blood and the Correlation Among these Factors in Diabetic Retinopathy Patients; Clinical Trial.Advanced pharmaceutical bulletin · 2026Article
- How Do Amyloid Pathology and Aberrant Neuronal Activity Disrupt Plasticity and Memory in Alzheimer's Disease?The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry · 2026Review
- De-2-hydroxyisobutyrylation of clusterin modulates neuropathology and memory deficits in an Alzheimer's disease mouse model.Cell communication and signaling : CCS · 2026Article
- RNA-binding activity of PHGDH drives amyloid-beta production in a human brain organoid model of sporadic Alzheimer's disease.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Dysregulated mRNA Translation in Alzheimer's Disease: Mechanisms, Therapeutic Opportunities, and Challenges for Clinical Translation.Clinical interventions in aging · 2026Review
- Bi-allelic variants in the ribosomal protein RPS6KC1 cause a complex neurodevelopmental disorder.American journal of human genetics · 2025Article
- Exploring the effects of squalene in the PERK/ATF4/eIF2α/CHOP signalling pathway in an in vitro Alzheimer Disease model and in silico approach.Metabolic brain disease · 2025Article
- Targeting Both Monomer and Oligomer with Fibrinogen Efficiently Suppresses Amyloid Fibril Formation and Cell Toxicity of Amyloid β 1-42.ACS chemical neuroscience · 2025Article
- Dual Nature of Mitochondrial Integrated Stress Response: Molecular Switches from Protection to Pathology.Genes · 2025Review
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- Organelle abnormalities in Alzheimer's disease.Organelle (Tucson, Ariz.) · 2025Article
- Key considerations for ELISA-based quantification of diverse amyloid beta forms in murine brain homogenates.Frontiers in neuroscience · 2025Article
- Predicting cellular adaptation proteins dependent on eIF2α regulation under stress conditions: Physiological and pathophysiological implications in neuronal function.Computational and structural biotechnology journal · 2025Article
- Eukaryotic initiation factors: central factor associating mRNA translational plasticity during neuropathic pain progression.Frontiers in neurology · 2025Review
- RTP801 interacts with the tRNA ligase complex and dysregulates its RNA ligase activity in Alzheimer's disease.Nucleic acids research · 2024Article
- Suppression of the amyloidogenic metabolism of APP and the accumulation of Aβ by alcadein α in the brain during aging.Scientific reports · 2024Article
- Glucose hypometabolism prompts RAN translation and exacerbates C9orf72-related ALS/FTD phenotypes.EMBO reports · 2024Article
186 more citing papers are in PubMed but not listed here.
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Authors and funding
16 authors at 5 institutions in 3 countries.
Funding
Abstract
beta-site APP cleaving enzyme-1 (BACE1), the rate-limiting enzyme for beta-amyloid (Abeta) production, is elevated in Alzheimer's disease (AD). Here, we show that energy deprivation induces phosphorylation of the translation initiation factor eIF2alpha (eIF2alpha-P), which increases the translation of BACE1. Salubrinal, an inhibitor of eIF2alpha-P phosphatase PP1c, directly increases BACE1 and elevates Abeta production in primary neurons. Preventing eIF2alpha phosphorylation by transfection with constitutively active PP1c regulatory subunit, dominant-negative eIF2alpha kinase PERK, or PERK inhibitor P58(IPK) blocks the energy-deprivation-induced BACE1 increase. Furthermore, chronic treatment of aged Tg2576 mice with energy inhibitors increases levels of eIF2alpha-P, BACE1, Abeta, and amyloid plaques. Importantly, eIF2alpha-P and BACE1 are elevated in aggressive plaque-forming 5XFAD transgenic mice, and BACE1, eIF2alpha-P, and amyloid load are correlated in humans with AD. These results strongly suggest that eIF2alpha phosphorylation increases BACE1 levels and causes Abeta overproduction, which could be an early, initiating molecular mechanism in sporadic AD.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.