MAFG as a Redox-Sensitive Node Linking Peripheral Immune Reprogramming to Cognitive Risk in the Sepsis-to-Alzheimer's Disease Continuum: Single-Cell Dissection and Adoptive-Transfer Validation.

backgroundSepsis survivors face an elevated long-term risk of Alzheimer's disease (AD), yet the peripheral pathways linking systemic immune activation to chronic neurodegeneration remain undefined. We mapped peripheral immune reprogramming across sepsis and AD and tested a candidate regulatory node.

methodsA single-cell atlas of peripheral immunity was built by integrating scRNA-seq from human sepsis and AD cohorts, using clustering, SCENIC regulatory-network inference and an exploratory pseudotime ordering. The resulting signature was validated in two clinical cohorts (ROC and survival analysis). MAFG-associated subpopulations and redox status were profiled in APP/PS1, cecal ligation and puncture (CLP) and composite models, and causality was tested by lentiviral MAFG knockdown and adoptive transfer into APP/PS1 recipients.

resultsPeripheral immunity was myeloid-skewed in sepsis and lymphoid-dominated in AD, with APP-expressing common myeloid progenitors (CMPs), dendritic cells (DCs), and platelets forming an APP-enriched compartment. A core transcription-factor network differed between disease states, yielding a four-gene signature (MAFG, NFIL3, RGS10, FOXO3) with cross-cohort diagnostic and prognostic value. MAFG was upregulated in septic patients and associated with poorer survival, subpopulation expansion, and systemic oxidative stress. Superimposed CLP aggravated amyloid deposition, microglial activation, and memory deficits in APP/PS1 mice, whereas MAFG silencing restored Aβ uptake and, on adoptive transfer, reduced amyloid burden, attenuated microgliosis, and preserved cognition.

conclusionsPeripheral immune states differ across the sepsis-to-AD spectrum and are captured by a MAFG-centered signature. Independent of any trajectory assumption, loss-of-function and adoptive-transfer experiments identify MAFG as a causal, redox-sensitive node constraining peripheral Aβ clearance and a candidate biomarker and therapeutic target in sepsis survivors.