ArticleNeurobiology of aging2014
PERK mediates eIF2α phosphorylation responsible for BACE1 elevation, CREB dysfunction and neurodegeneration in a mouse model of Alzheimer's disease.
Article in Neurobiology of aging, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 96 papers.
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Who cites it
96 citing papers in PubMed, 168 citations in OpenAlex.
- Dissecting the cell biology of the ISR in cognitive disorders at the single-cell resolution.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Alzheimer's Disease as a Multi-Layer Network Disorder: A Systems Biology Framework Integrating Multi-Omics Mechanisms.Biomedicines · 2026Review
- Filamin A phosphorylation at S2152: a molecular switch fueling cancer and neurodegeneration.Cell communication and signaling : CCS · 2026Review
- 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
- Navigating the landscape of protein folding and proteostasis: from molecular chaperones to therapeutic innovations.Signal transduction and targeted therapy · 2025Review
- Diabetic retinopathy and Alzheimer's disease: Convergence of the unfolded protein response in neurodegeneration.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Review
- N-acetyl L-cysteine and Growth Factors Impede Endoplasmic Reticulum Stress and Inflammatory Responses in Astrocytes to Amyloid-β in Serum-free Culture.Annals of neurosciences · 2025Article
- RNA dysregulation in neurodegenerative diseases.The EMBO journal · 2025Review
- BACE1 at the crossroads of a vicious circle between Alzheimer's disease and diabetes mellitus.Frontiers in dementia · 2025Review
- Quantitative Imaging of Regional Cerebral Protein Synthesis in Clinical Alzheimer's Disease by [Molecular imaging and biology · 2024Article
- Haploinsufficiency and Alzheimer's Disease: The Possible Pathogenic and Protective Genetic Factors.International journal of molecular sciences · 2024Review
- Endoplasmic reticulum stress in diseases.MedComm · 2024Review
- Downregulation of ATF-4 Attenuates the Endoplasmic Reticulum Stress-Mediated Neuroinflammation and Cognitive Impairment in Experimentally Induced Alzheimer's Disease Model.Molecular neurobiology · 2024Article
- The integrated stress response in brain diseases: A double-edged sword for proteostasis and synapses.Current opinion in neurobiology · 2024Review
- Genetic Variations in EIF2AK3 are Associated with Neurocognitive Impairment in People Living with HIV.Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology · 2024Article
- Article
- Therapeutic Potential of Targeting the PERK Signaling Pathway in Ischemic Stroke.Pharmaceuticals (Basel, Switzerland) · 2024Review
- Astrocytic deletion of protein kinase R-like ER kinase (PERK) does not affect learning and memory in aged mice but worsens outcome from experimental stroke.Journal of neuroscience research · 2023Article
- The PERK pathway: beneficial or detrimental for neurodegenerative diseases and tumor growth and cancer.Human molecular genetics · 2023Review
- Measurement of Protein Synthesis Rate in Rat by [Molecular imaging and biology · 2023Article
36 more citing papers are in PubMed but not listed here.
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
Emerging evidence suggests that aberrant phosphorylation of eukaryotic initiation factor-2α (eIF2α) may induce synaptic failure and neurodegeneration through persistent translational inhibition of global protein synthesis. However, elevated phospho-eIF2α also paradoxically causes translational activation of a subset of messenger RNAs such as the β-secretase enzyme, β-site APP-cleaving enzyme 1 (BACE1) and cAMP response element binding protein (CREB) repressor, activating transcription factor 4 (ATF4). Therefore, we tested whether genetic reduction of the eIF2α kinase PERK may prevent these deleterious events and mitigate Alzheimer's disease (AD)-like neuropathology and cognitive impairments in the 5XFAD mouse model. PERK haploinsufficiency blocked overactivation of the PERK-eIF2α pathway, as evidenced by significant reductions in phosphorylation of PERK and eIF2α, in 5XFAD mice. PERK haploinsufficiency was sufficient to rescue memory deficits and cholinergic neurodegeneration in this AD model. Notably, PERK haploinsufficiency also prevented BACE1 elevations, resulting in reduced levels of amyloid-β peptides and plaque burden in 5XFAD mice. Moreover, CREB dysfunction was restored in PERK(+/-)·5XFAD mice concomitant with reversal of ATF4 upregulation. Together, these findings suggest that PERK may be a disease-modifying therapeutic target to prevent multiple memory-disrupting mechanisms associated with 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.