ArticleNeuron2025
Selective removal of astrocytic PERK protects against glymphatic impairment and decreases toxic aggregation of β-amyloid and tau.
Article in Neuron, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed.
- Glymphatic system dysfunction: a link between sleep disorders and neurodegeneration.Psychopharmacology · 2026Review
- Regional astrocyte dysregulation and altered glymphatic-related markers in Alzheimer's disease frontal cortex.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- Distinct cell type-specific mechanisms underlie cognitive dysfunction during persistent integrated stress response activation.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- AQP4-dependent enhancement of glymphatic function attenuates tau pathology and neurodegeneration in PS19 mice.Molecular neurodegeneration · 2026Article
- HD-tDCS Restores Perivascular AQP4 Polarization via PPARγ Modulation to Enhance Glymphatic Clearance After Intracerebral Hemorrhage in Mice.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Protein kinase CK2α' as a dual modulator of neuroimmune signaling and synaptic dysfunction in tauopathy.Translational neurodegeneration · 2026Article
- Progressive Supranuclear Palsy PERK Haplotype B Selectively Translates DLX1 Promoting Tau Toxicity.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2026Article
- Impact of early glymphatic disorders on the development of vascular dementia.BMC medical imaging · 2026Article
- Astrocytic PERK Deficiency Drives Prefrontal Circuit Dysfunction and Depressive-Like Behaviors.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Silmitasertib, an FDA-designated orphan CK2 inhibitor, ameliorates neuropathology and motor dysfunction in a Huntington's disease mouse model.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2026Article
- Association between glymphatic dysfunction and glucose hypometabolism in chronic disorders of consciousness: a multimodal PET/MRI study.Brain communications · 2026Article
- Association of Glymphatic Dysfunction with Cognitive Performance in Type 2 Diabetes Mellitus and Prediabetes.Neuroendocrinology · 2026Article
- Dysregulated mRNA Translation in Alzheimer's Disease: Mechanisms, Therapeutic Opportunities, and Challenges for Clinical Translation.Clinical interventions in aging · 2026Review
- Protein kinase CK2α' as a dual modulator of immune signaling and synaptic dysfunction in Tauopathy.bioRxiv : the preprint server for biology · 2025Article
- Silmitasertib, an FDA-designated orphan CK2 Inhibitor, ameliorates neuropathology and motor dysfunction in a Huntington's disease mouse model.bioRxiv : the preprint server for biology · 2025Article
- Eukaryotic initiation factors: central factor associating mRNA translational plasticity during neuropathic pain progression.Frontiers in neurology · 2025Review
- ER stress sensors at the ER-mitochondrial interface, controlling mitochondrial health in neurodegenerative diseases.Frontiers in neuroscience · 2025Review
Corrections and comments
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Authors and funding
6 authors.
Funding
Abstract
Dysfunction of the glymphatic system, a brain-wide waste clearance network, is strongly linked to Alzheimer's disease (AD) and the accumulation of β-amyloid (Aβ) and tau proteins. Here, we identify an astrocytic signaling pathway that can be targeted to preserve glymphatic function and mitigate neurotoxic protein buildup. Analysis of astrocytes from both human AD brains and two transgenic mouse models (5XFAD and PS19) reveals robust activation of the protein kinase RNA-like endoplasmic reticulum (ER) kinase (PERK)-α subunit of eukaryotic initiation factor 2 (eIF2α) branch of the unfolded protein response. Chronic PERK activation suppresses astrocytic protein synthesis and, through casein kinase 2 (CK2)-dependent mechanisms, disrupts the perivascular localization of aquaporin-4 (AQP4), a water channel essential for glymphatic flow. Importantly, astrocyte-specific PERK deletion or pharmacological inhibition restores AQP4 localization, enhances glymphatic clearance, reduces Aβ and tau pathology, and improves cognitive performance in mice. These findings highlight the critical role of the astrocytic PERK-CK2-AQP4 axis in glymphatic dysfunction and AD pathogenesis, positioning this pathway as a promising therapeutic target.
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Registered trials
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 Socratic graph.