ArticleAging cell2025
Neuronal cathepsin S increases neuroinflammation and causes cognitive decline via CX3CL1-CX3CR1 axis and JAK2-STAT3 pathway in aging and Alzheimer's disease.
Article in Aging cell, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers, 1 of them a synthesis that pooled it.
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Who cites it
31 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Differential effects of environmental enrichment and physical exercise on glial biology in aging and aging-related conditions: a systematic review.Frontiers in cellular neuroscience · 2026Pooled it
- Estrogen deprivation exacerbates Alzheimer's disease pathology through neuronal CTSS signaling.Journal of neuroinflammation · 2026Article
- Machine Learning-Based Cytokine Endotyping of Thyroid Eye Disease.Investigative ophthalmology & visual science · 2026Article
- Neuroinflammation in Alzheimer's and Parkinson's diseases: pathogenic mechanisms and therapeutic strategies.Translational neurodegeneration · 2026Review
- The Exercise-CTSS-AD Axis: a novel framework for understanding exercise-induced neuroprotection in Alzheimer's disease.Metabolic brain disease · 2026Review
- Aberrant CX3CL1-CX3CR1 Signaling Reprograms Microglial Exosome Secretion via KIFC2 to Drive Cognitive Impairment in Chronic Pain.International journal of molecular sciences · 2026Article
- CX3CL1 in Early Detection of Alzheimer's Disease: Plasma Dynamics Across Age and Disease Stages.Annals of clinical and translational neurology · 2026Article
- S100A14 in Tumor-Derived EVs Targets PIAS3 to Reprogram Astrocytes and Induce Immunosuppressive Microenvironment Promoting Brain Metastasis and Germacrone Reversal Effect.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Beyond biochemical cascades: novel bio-mechanical and epigenetic paradigms of glial SASP in brain aging.Metabolic brain disease · 2026Review
- Cathepsins as Core Players in Obesity Pathogenesis: Emerging Therapeutic Targets.Biomolecules · 2026Review
- Unveiling an ALS Blood Transcriptomic Signature: A Machine Learning Classifier Distinct from Neurodegenerative Controls.Neuroinformatics · 2026Article
- TREM2 deficiency causes region-specific brain effects in a mouse model of cerebral amyloid angiopathy.bioRxiv : the preprint server for biology · 2026Article
- The Bidirectional Regulatory Role of Neuroimmune Interaction in Neurodevelopment and Neurodegenerative Diseases.The Yale journal of biology and medicine · 2026Review
- The spleen-brain axis in Alzheimer's disease and related dementias: Integrating immune and metabolic regulation.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Review
- Chronic inflammation promotes gastric cancer progression via ADAM10-mediated cleavage of CX3CL1.Scientific reports · 2026Article
- Intermittent fasting and immune aging: implications for immunosenescence, inflammaging, neuroinflammation, and frailty.Frontiers in nutrition · 2026Review
- Proteome-wide Mendelian randomization and colocalization analyses identify potential biomarkers for schizophrenia.Frontiers in psychiatry · 2026Article
- Analysis of the Immunoinflammatory Microenvironment Characteristics of Epilepsy Based on Single-Cell Transcriptomics.Journal of inflammation research · 2026Review
- Targeting Cathepsins in Neurodegeneration: Biochemical Advances.Biomedicines · 2025Review
- Multi-omics reveals the impact of Clonorchis sinensis infection on mouse gut microbiota, metabolomics and transcriptomics.BMC microbiology · 2025Article
Corrections and comments
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Authors and funding
18 authors.
Funding
Abstract
Aging is an intricate process involving interactions among multiple factors, which is one of the main risks for chronic diseases, including Alzheimer's disease (AD). As a member of cysteine protease, cathepsin S (CTSS) has been implicated in inflammation across various diseases. Here, we investigated the role of neuronal CTSS in aging and AD started by examining CTSS expression in hippocampus neurons of aging mice and identified a significant increase, which was negatively correlated with recognition abilities. Concurrently, we observed an elevation of CTSS concentration in the serum of elderly people. Transcriptome and fluorescence-activated cell sorting (FACS) results revealed that CTSS overexpression in neurons aggravated brain inflammatory milieu with microglia activation to M1 pro-inflammatory phenotype, activation of chemokine C-X3-C-motif ligand 1 (CX3CL1)-chemokine C-X3-C-motif receptor 1 (CX3CR1) axis and janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) pathway. As CX3CL1 is secreted by neurons and acts on the CX3CR1 in microglia, our results revealed for the first time the role of neuron CTSS in neuron-microglia "crosstalk." Besides, we observed elevated CTSS expression in multiple brain regions of AD patients, including the hippocampus. Utilizing CTSS selective inhibitor, LY3000328, rescued AD-related pathological features in APP/PS1 mice. We further noticed that neuronal CTSS overexpression increased cathepsin B (CTSB) activity, but decreased cathepsin L (CTSL) activity in microglia. Overall, we provide evidence that CTSS can be used as an aging biomarker and plays regulatory roles through modulating neuroinflammation and recognition in aging and AD process.
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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 OpenQuestion graph.