ArticleJournal of advanced research2026
Age-dependent elevation of Nr4a1 attenuates PI3K/AKT/GSK3β pathway and mediates tau hyperphosphorylation and cognitive impairments.
Article in Journal of advanced research, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed.
- Intranasal Artesunate Ameliorates Hippocampal LFP Abnormalities and Cellular Apoptosis in APP/PS1 Mice via a Mechanism Involving GHRH/PI3K/AKT Signaling.Molecular neurobiology · 2026Article
- Mechanisms of Brain Aging and Their Links to Alzheimer's and Parkinson's Disease Pathology.International journal of molecular sciences · 2026Review
- PYCR1 induces ferroptosis via the PI3K/Akt signaling pathway to regulate the proliferation and migration of osteosarcoma.Translational oncology · 2026Article
- Aging-Related Changes in the Injury Response of the Peripheral Nervous System.Neuroscience bulletin · 2026Review
- Cistanoside A decreases Tau hyperphosphorylation and neuronal apoptosis through the AKT/GSK3β pathway in okadaic acid-induced in vivo and in vitro models of Alzheimer's disease.Molecular biology reports · 2026Article
- Baicalein alleviates Alzheimer's disease pathology in AD models by activating the PI3K/AKT/GSK3β pathway to inhibit neuronal apoptosis.Scientific reports · 2026Article
- NR4A1 mediates chemotherapy‑induced senescence via the PI3K/AKT pathway in gastric cancer cells.Oncology reports · 2026Article
- Nr4a1 regulates microglia overactivation-mediated neuroinflammation to ameliorate cognitive impairment in trigeminal neuralgia rats.The journal of headache and pain · 2026Article
- Engram cell vulnerability in neurodegeneration: from mechanistic insights to therapeutic horizons.Frontiers in aging neuroscience · 2026Review
- Peripheral blood microarray-based transcriptomic and epigenetic analyses identify immune, inflammation, and metabolic dysregulation in Alzheimer's disease.NPJ dementia · 2026Article
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Authors and funding
13 authors.
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Abstract
introductionTau hyperphosphorylation exhibited in Alzheimer's brains is also commonly observed in aging process, however, the molecular mechanism underlying tau hyperphosphorylation in aging is largely unknown. The nuclear receptor subfamily 4 group A (Nr4a1) has been implicated in various pathophysiological processes including neurodegeneration, and was found to be increased in Alzheimer's brains.
objectivesOur study aims to investigate whether and how Nr4a1 promotes age-related tau hyperphosphorylation and cognitive decline.
methodsFirstly, we examined Nr4a1 levels in hippocampus of Alzheimer's patients, SAMP8 and aged mice. Tau phosphorylation levels were evaluated in hippocampal Nr4a1-overexpressed wild-type mice. Bulk RNA sequencing was performed to gain insight into the molecular mechanism by which elevated Nr4a1 levels drive tau hyperphosphorylation. shNr4a1 viruses were used to knockdown Nr4a1 in senescent neurons and hippocampus of SAMP8 mice, further, tau phosphorylation levels and cognitive function were evaluated. Molecular docking studies were conducted to explore the interaction between Nr4a1 and AKT.
resultsOur findings revealed that Nr4a1 expression is elevated in the hippocampus of Alzheimer's patients, as well as in the hippocampi of SAMP8 mice and aged mice. Notably, in SAMP8 mice, Nr4a1 expression increased in an age-dependent manner, suggesting a positive correlation between Nr4a1 levels and aging. Further investigation showed that hippocampal overexpression of Nr4a1 in wild-type mice led to tau hyperphosphorylation and cognitive dysfunction, which could be rescued by Nr4a1 knockdown in SAMP8 mice. By means of bulk RNA sequencing, we demonstrated that Nr4a1 induced tau hyperphosphorylation through the inhibition of PI3K/AKT/GSK-3β pathway. Furthermore, blocking Nr4a1-AKT interactions using competitive peptides reversed tau hyperphosphorylation.
conclusionThese results supported the hypothesis that age-dependent upregulation of Nr4a1 attenuated PI3K/AKT/GSK-3β pathway, leading to tau hyperphosphorylation and cognitive decline. Nr4a1 may represent a promising therapeutic target for mitigating age-related cognitive impairments.
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