CNS-Peripheral Cytokine Compartmentalization

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Why do systemic anti-inflammatory drugs fail in AD despite cardiovascular efficacy if neuroinflammation is central?

The debate noted clinical failures of TNF-α and IL-6 inhibitors in AD despite their cardiovascular success and shared inflammatory pathways. This paradox suggests unknown mechanistic differences that could inform therapeutic design. Source: Debate session sess_SDA-2026-04-04-gap-neuro-microglia-early-ad-20260404 (Analysis: SDA-2026-04-04-gap-neuro-microglia-early-ad-20260404)

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graph TD
    TNFRSF1B["TNFRSF1B"] -->|regulates| synaptic_plasticity["synaptic_plasticity"]
    LRP1["LRP1"] -->|regulates| blood_brain_barrier["blood_brain_barrier"]
    SLC16A7["SLC16A7"] -->|modulates| lactate_shuttling["lactate_shuttling"]
    AQP4["AQP4"] -->|regulates| glymphatic_system["glymphatic_system"]
    NLRP3["NLRP3"] -->|activates| inflammasome_activation["inflammasome_activation"]
    neuroinflammation["neuroinflammation"] -->|causes| alzheimer_disease["alzheimer_disease"]
    TNF["TNF"] -->|enhances| neuroinflammation_1["neuroinflammation"]
    IL6["IL6"] -->|enhances| neuroinflammation_2["neuroinflammation"]
    NLRP3_3["NLRP3"] -->|enhances| neuroinflammation_4["neuroinflammation"]
    TNF_5["TNF"] -->|regulates| glymphatic_clearance["glymphatic_clearance"]
    IL6_6["IL6"] -->|regulates| glymphatic_clearance_7["glymphatic_clearance"]
    TNF_8["TNF"] -->|regulates| glucose_metabolism["glucose_metabolism"]
    style TNFRSF1B fill:#ce93d8,stroke:#333,color:#000
    style synaptic_plasticity fill:#4fc3f7,stroke:#333,color:#000
    style LRP1 fill:#ce93d8,stroke:#333,color:#000
    style blood_brain_barrier fill:#4fc3f7,stroke:#333,color:#000
    style SLC16A7 fill:#ce93d8,stroke:#333,color:#000
    style lactate_shuttling fill:#81c784,stroke:#333,color:#000
    style AQP4 fill:#ce93d8,stroke:#333,color:#000
    style glymphatic_system fill:#81c784,stroke:#333,color:#000
    style NLRP3 fill:#ce93d8,stroke:#333,color:#000
    style inflammasome_activation fill:#81c784,stroke:#333,color:#000
    style neuroinflammation fill:#4fc3f7,stroke:#333,color:#000
    style alzheimer_disease fill:#ef5350,stroke:#333,color:#000
    style TNF fill:#ce93d8,stroke:#333,color:#000
    style neuroinflammation_1 fill:#4fc3f7,stroke:#333,color:#000
    style IL6 fill:#ce93d8,stroke:#333,color:#000
    style neuroinflammation_2 fill:#4fc3f7,stroke:#333,color:#000
    style NLRP3_3 fill:#ce93d8,stroke:#333,color:#000
    style neuroinflammation_4 fill:#4fc3f7,stroke:#333,color:#000
    style TNF_5 fill:#ce93d8,stroke:#333,color:#000
    style glymphatic_clearance fill:#81c784,stroke:#333,color:#000
    style IL6_6 fill:#ce93d8,stroke:#333,color:#000
    style glymphatic_clearance_7 fill:#81c784,stroke:#333,color:#000
    style TNF_8 fill:#ce93d8,stroke:#333,color:#000
    style glucose_metabolism fill:#81c784,stroke:#333,color:#000

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