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bioRxiv · 10.1101/2025.05.10.653288

Transcriptomic analysis reveals new reparative mechanisms of SCF and GCSF - reduced neuropathology in aged APPPS1 mice

Addo, A.·Li, B.·Murikinati, S.·Gardner, R.·Zhao, L.-R.
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Abstract

Alzheimers Disease (AD) is a neurodegenerative disease characterized by amyloid plaque deposition, tau hyperphosphorylation, neuroinflammation, and cognitive decline. Our previous studies showed that combined treatment with stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF) reduces AD pathology in APP/PS1 mice. This study aimed to explore the molecular mechanism underlying SCF+G-CSFs therapeutic effects using transcriptomic analysis. Aged APP/PS1 mice received daily subcutaneous injections of SCF+G-CSF or vehicle for 12 days. RNA was extracted from brain tissue on day 13 for gene chip analysis. Age-matched wild-type (WT) mice served as controls. Data were analyzed using TAC, STRING v12.0, Reactome, and ShinyGO 0.77. A total of 45,037 differentially expressed genes (DEGs) were detected. Twenty-seven DEGs met a [≥]2-fold threshold in SCF+G-CSF-treated vs. vehicle-treated APP/PS1 mice; 89 DEGs met this threshold in APP/PS1 vs. WT mice. SCF+G-CSF treatment upregulated six immune-related genes (S100a8, S100a9, Ngp, Lcn2, Ltf, and Camp) associated with amyloid clearance, immune cell recruitment, and repair. Pathway analysis showed downregulation of IL-2, IL-4, IL-7, and EGFR1, and upregulation of IL-17 signaling, suggesting modulation of both innate and adaptive immunity. Notably, SCF+G-CSF downregulated several oncogenes, including Cbl, Akap9, Kcnq1ot1, and Snhg11, highlighting an overlap between cancer and AD-related pathways. SCF+G-CSF also promoted NADPH oxidase activation via Rho GTPases and showed >400-fold enrichment in metal ion sequestration, indicating potential metal chelation effects. These findings suggest that SCF+G-CSF treatment modifies immune and metabolic pathways, reduces AD pathology, and highlights new therapeutic targets involving inflammation, metal homeostasis, and oncogenic signaling.

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Addo, A., Li, B., Murikinati, S., Gardner, R., Zhao, L.-R.. 2025-05-15. Transcriptomic analysis reveals new reparative mechanisms of SCF and GCSF - reduced neuropathology in aged APPPS1 mice. https://doi.org/10.1101/2025.05.10.653288

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