ArticleAging cell2021
FoxO3 deficiency in cortical astrocytes leads to impaired lipid metabolism and aggravated amyloid pathology.
Article in Aging cell, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers, 1 of them a synthesis that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
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
25 citing papers in PubMed, 1 synthesis or guideline pooled it, 39 citations in OpenAlex.
- The Role of Astrocytes in Synapse Loss in Alzheimer's Disease: A Systematic Review.Frontiers in cellular neuroscience · 2022Pooled it
- FOXO family and neurodegenerative diseases: Mechanisms of action and therapeutic potential.Redox biology · 2026Review
- Luteolin in Safflower Leaves Suppresses Microglial Inflammation Through FOXO3-MediatedAntioxidants (Basel, Switzerland) · 2025Article
- Discovery of a brain penetrant SGK1 inhibitor using a ligand- and structure-based virtual screening methodology.Journal of enzyme inhibition and medicinal chemistry · 2025Article
- PIEZO1 gain-of-function mutation drives cardiomyopathy by disrupting myocardial lipid homeostasis besides iron overload.Science advances · 2025Article
- Transcriptional Dysregulation of Autophagy in Aging and Potential Interventions: Insights Into TFEB and FOXOs.Frontiers in bioscience (Landmark edition) · 2025Review
- Proinflammatory transcriptomic and kinomic alterations in astrocytes derived from patients with familial Alzheimer's disease.Brain, behavior, & immunity - health · 2025Article
- Regulation of endothelial cell senescence via the miR-217/FOXO3 axis.Biogerontology · 2025Article
- Interrogating mediators of single-cell transcriptional changes in the acute damaged cerebral cortex: Insights into endothelial-astrocyte interactions.Molecular and cellular neurosciences · 2025Article
- Astrocytes Lingering at a Crossroads: Neuroprotection and Neurodegeneration in Neurocognitive Dysfunction.International journal of biological sciences · 2025Review
- Neuroglia and brain energy metabolism.Handbook of clinical neurology · 2025Review
- Complement C3aR signaling: Immune and metabolic modulation and its impact on Alzheimer's disease.European journal of immunology · 2024Review
- MicroRNAs-associated with FOXO3 in cellular senescence and other stress responses.Biogerontology · 2024Review
- Hesperetin activates CISD2 to attenuate senescence in human keratinocytes from an older person and rejuvenates naturally aged skin in mice.Journal of biomedical science · 2024Article
- FOXO transcription factors as mediators of stress adaptation.Nature reviews. Molecular cell biology · 2024Review
- The role of glial autophagy in Alzheimer's disease.Molecular psychiatry · 2023Review
- FOXO family isoforms.Cell death & disease · 2023Review
- Klotho increases antioxidant defenses in astrocytes and ubiquitin-proteasome activity in neurons.Scientific reports · 2023Article
- Bioorthogonal Stimulated Raman Scattering Imaging Uncovers Lipid Metabolic Dynamics inGEN biotechnology · 2023Article
- The landscape of meLife · 2023Article
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
Abstract
The rise of life expectancy of the human population is accompanied by the drastic increases of age-associated diseases, in particular Alzheimer's disease (AD), and underscores the need to understand how aging influences AD development. The Forkhead box O transcription factor 3 (FoxO3) is known to mediate aging and longevity downstream of insulin/insulin-like growth factor signaling across species. However, its function in the adult brain under physiological and pathological conditions is less understood. Here, we report a region and cell-type-specific regulation of FoxO3 in the central nervous system (CNS). We found that FoxO3 protein levels were reduced in the cortex, but not hippocampus, of aged mice. FoxO3 was responsive to insulin/AKT signaling in astrocytes, but not neurons. Using CNS Foxo3-deficient mice, we reveal that loss of FoxO3 led to cortical astrogliosis and altered lipid metabolism. This is associated with impaired metabolic homoeostasis and β-amyloid (Aβ) uptake in primary astrocyte cultures. These phenotypes can be reversed by expressing a constitutively active FOXO3 but not a FOXO3 mutant lacking the transactivation domain. Loss of FoxO3 in 5xFAD mice led to exacerbated Aβ pathology and synapse loss and altered local response of astrocytes and microglia in the vicinity of Aβ plaques. Astrocyte-specific overexpression of FOXO3 displayed opposite effects, suggesting that FoxO3 functions cell autonomously to mediate astrocyte activity and also interacts with microglia to address Aβ pathology. Our studies support a protective role of astroglial FoxO3 against brain aging and AD.
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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.