Neuroimmune Crosstalk Between Periodontitis and Alzheimer’s Disease Revealed by Single-Nucleus and Single-Cell Transcriptomics

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Abstract Systemic inflammation is increasingly recognized as a contributor to neuroinflammation and neurodegenerative disease progression. Periodontitis, a chronic oral inflammatory disease, has been epidemiologically and experimentally linked to Alzheimer’s disease (AD), yet its impact on brain cellular states at single-cell resolution remains unclear. We investigated the effects of experimental periodontitis and acute exposure to Fusobacterium nucleatum-derived cell-free lysate on brain cellular composition and transcriptional profiles using complementary approaches. Experimental periodontitis was induced in C57BL/6 and 5×FAD mice using a bi-stimulus model that combined ligature placement with repeated F. nucleatum inoculation. For acute central nervous system (CNS) responses, F. nucleatum-derived cell-free lysate was administered intracerebroventricularly into WT mice and whole-brain single-nucleus RNA sequencing was performed one-hour post-injection. For chronic disease-relevant responses, CD11b+ myeloid-enriched and ACSA-2+ glial-enriched cells were isolated from 4-month-old WT_Healthy, and 5×FAD healthy (AD_Healthy) and 5×FAD periodontitis (AD_Perio) mice for single-cell RNA-seq. GSEA was performed using HALLMARK, GO BP, and Reactome gene set collections. Sequencing datasets generated for this study have been deposited in the Gene Expression Omnibus under accession numbers GSE334979, GSE335285, and GSE335179. Experimental periodontitis produced alveolar bone loss, elevated brain IL-1β and TNF-α, and morphological microglial activation. Intracerebroventricular F. nucleatum cell-free lysate elevated the neuronal excitatory/inhibitory ratio and broadly remodeled predicted intercellular ligand-receptor communication networks, resembling an early AD-like neuronal imbalance signature. scRNA-seq identified seven cell populations in the CD11b+ myeloid cells. 5×FAD genotype drove progressive homeostatic microglial contraction and marked disease-associated macrophage (DAM) expansion relative to WT_Healthy. In the AD_Perio versus AD_Healthy comparison, experimental periodontitis superimposed on amyloid pathology with convergent TNF-α/NF-κB upregulation across DAMs, border-associated macrophages (BAMs), and early activated microglia. Within early activated microglia, 5×FAD mice shifted toward later pseudotime relative to WT_Healthy, with a modest further enrichment in AD_Perio compared with AD_Healthy. In the ACSA-2+ compartment, 5×FAD drove progressive contraction of Emx2+ cortical/regional astrocytes, independently of periodontitis. A broad suppression of metabolic and biosynthetic pathways across all five glial subtypes was observed in 5×FAD mice. Periodontitis selectively reversed this suppression and upregulated cholesterol homeostasis in myelinating oligodendrocytes, homeostatic astrocytes, and cortical Emx2⁺ astrocytes. These findings provide a multi-cellular and molecular framework linking periodontal inflammation to neuroinflammatory and neuronal alterations relevant to early AD pathology, suggesting myeloid NF-κB activation, altered microglial trajectory states, BAM responsiveness to peripheral inflammatory challenge, cortical astrocyte cholesterol and inflammatory pathway regulation, and oligodendrocyte stress vulnerability as key cellular mechanisms through which systemic oral inflammation may contribute to AD-associated brain pathology. Graphical Abstract Graphic abstract illustrating the impact of periodontitis on brain cells: The acute model shows altered E/I neuronal ratios and remodeled cell-cell communication following i.c.v. injection of Fusobacterium nucleatum-derived lysate. The chronic model depicts transcriptional changes in myeloid and glial cells under amyloid pathology alone and with the addition of periodontitis.

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