"For decades, Alzheimer's research focused almost exclusively on amyloid-beta and tau deposits, while inflammation was considered a side effect," says Heppner. "Only recently have we begun to recognize that inflammatory processes may be a primary driver of disease progression."

A groundbreaking study published in Nature Aging reveals new insights into Alzheimer's pathology. Researchers from Charité – Universitätsmedizin Berlin and the Max Delbrück Center have identified the inflammatory cytokine IL-12 as a central driver of neuroimmune dysregulation in AD. This discovery establishes critical theoretical foundations for developing targeted IL-12 therapies.

Figure 1. Title and Journal Information

Alzheimer's disease (AD) is characterized by amyloid-beta plaques, tau protein tangles, and neuroinflammation. Emerging evidence suggests the IL-12/IL-23 signaling pathway plays a significant role in AD pathogenesis. Although sharing the p40 subunit, IL-12 and IL-23 demonstrate distinct receptor distribution and functional mechanisms in AD that remain poorly understood. Through animal models and human tissue analysis, the German research team has elucidated IL-12's central role in AD pathology, opening new therapeutic avenues.

Figure 2. Experimental Design and Principles

IL-12

IL-12 is a heterodimeric cytokine comprising p35 (IL-12α) and p40 (IL-12β) subunits linked via disulfide bonds. The p40 subunit serves dual roles, combining with p35 to form IL-12 or pairing with IL-23's p19 subunit. IL-12 activates STAT4 phosphorylation through binding to cell surface receptors, driving Th1 immune responses and promoting pro-inflammatory factors like interferon-γ.

Figure 3. IL-12 Structure and Mechanism

Research team's discovery

The research team discovered distinctive IL-12 receptor expression patterns in both Alzheimer's disease model mice (APPPS1) and human patient samples, with neurons and oligodendrocytes showing specific upregulation of IL12RB1/IL12RB2 receptor subunits. Notably, IL-23 receptors were virtually undetectable in these cells.

Genetic ablation experiments demonstrated that IL-12 signaling deficiency significantly reduced amyloid-beta deposition, whereas blocking the IL-23 pathway produced no comparable effect.

Figure 4. Deletion of IL-12-specific receptor subunit IL12Rβ2 results in reduction of amyloid burden.

Single-cell sequencing further revealed that IL-12 disrupts oligodendrocyte homeostasis, leading to a dramatic depletion of mature oligodendrocytes in the hippocampal region—a pathological phenomenon fully reversed in IL-12 knockout mice.

Mechanistic investigations identified that IL-12 activation of the STAT4 signaling pathway triggers oligodendrocyte apoptosis, resulting in myelin structural abnormalities. Concurrently, this pathway drives reductions in hippocampal GABAergic interneuron populations and dysregulates synaptic plasticity-associated genes (e.g., Erbb4, Rarb). Intriguingly, while IL-12 deficiency did not directly alter microglial inflammatory profiles, it indirectly enhanced amyloid-beta clearance capacity by restoring oligodendrocyte functionality. These findings collectively implicate IL-12 as a pivotal disruptor of neuron-glia interactions in AD pathology.

Figure 5. IL-12p70 or IL-12p80 stimulation of murine embryonic primary myelinating culture results in reduced neurofilament and myelination.

This study establishes IL-12 as a key mediator of neuroimmune dysregulation in AD. Its receptor-specific activation in neurons and oligodendrocytes disrupts cellular homeostasis through STAT4 signaling, causing myelin defects, GABAergic interneuron loss, and synaptic dysfunction. These findings provide the first definitive evidence positioning IL-12 as a central pathogenic driver, informing precision therapeutic strategies.

Abinscience

Abinscience specializes in developing high-quality bioreagents for global researchers. Leveraging ProteoGenix's R&D expertise and stringent quality control, we offer innovative solutions across autoimmune diseases, neurobiology, and immune target discovery. Our product portfolio features:

• High-specificity IL-12 antibodies
• Recombinant proteins with >95% purity
• Customizable assay kits
• Functional study tools for neurological research

IL-12-related product

Antibody:

Protein:

Alzheimer's disease-related product

Antibody:

Protein:

Reference:

Schneeberger, Shirin et al. “Interleukin-12 signaling drives Alzheimer's disease pathology through disrupting neuronal and oligodendrocyte homeostasis.” Nature aging, 10.1038/s43587-025-00816-2. 13 Mar. 2025, doi:10.1038/s43587-025-00816-2