Hypothesis Comparison

graph TD
    A["Neuroinflammation<br/>IL-1beta, TNF-alpha, C3"] --> B["Astrocyte Reactivity<br/>JAK-STAT3 Activation"]
    B --> C["GFAP Upregulation<br/>Reactive Phenotype"]

    C --> D["SLC16A1/MCT1<br/>Downregulation -1.9x"]
    C --> E["SLC16A3/MCT4<br/>Upregulation +2.3x"]
    C --> F["Warburg-like Shift<br/>HK2up PKM2up LDHAup"]

    D --> G["Loss of Demand-Matched<br/>Lactate Export"]
    E --> H["High-Threshold<br/>Pulsatile Release"]
    F --> I["Intracellular Lactate<br/>Accumulation"]

    G --> J["Metabolic Uncoupling<br/>from Neuronal Demand"]
    H --> J
    I --> H

    J --> K["Neuronal Energy<br/>Deficit During LTP"]
    K --> L["Synaptic Dysfunction<br/>fEPSPdown 30-40%"]
    L --> M["Memory Impairment<br/>Encoding Failure"]
    M --> N["Cognitive Decline"]

    O["Amyloid-beta Plaques"] --> A
    P["Complement Activation<br/>C1q, C3"] --> A

    style J fill:#ff6b6b,stroke:#c92a2a,color:#fff
    style N fill:#ff8787,stroke:#c92a2a,color:#fff
    style D fill:#ffd43b,stroke:#f08c00,color:#000
    style E fill:#ffd43b,stroke:#f08c00,color:#000
    style B fill:#748ffc,stroke:#364fc7,color:#fff

graph TD
    A["Amyloid-beta plaques<br/>and inflammatory signals"] --> B["Microglial activation<br/>to DAM phenotype"]
    B --> C["ACSL4 gene<br/>transcriptional upregulation"]
    C --> D["ACSL4 protein<br/>enzymatic activity increase"]
    D --> E["Arachidonic acid esterification<br/>to arachidonyl-CoA"]
    D --> F["Adrenic acid esterification<br/>to adrenoyl-CoA"]
    E --> G["PE-AA synthesis<br/>in membrane phospholipids"]
    F --> H["PE-AdA synthesis<br/>in membrane phospholipids"]
    G --> I["PUFA-PE membrane<br/>substrate accumulation"]
    H --> I
    B --> J["GPX4 downregulation<br/>and GSH depletion"]
    I --> K["Ferroptotic priming<br/>state establishment"]
    J --> K
    L["Iron accumulation<br/>in brain tissue"] --> M["Fenton reaction<br/>hydroxyl radical generation"]
    M --> N["Lipid peroxidation<br/>of PUFA-PE substrates"]
    K --> N
    N --> O["Membrane integrity<br/>disruption and damage"]
    O --> P["Microglial ferroptotic<br/>cell death execution"]
    P --> Q["Pro-inflammatory<br/>mediator release"]
    P --> R["Reduced phagocytic<br/>clearance capacity"]
    Q --> S["Neuroinflammation<br/>amplification"]
    R --> T["Amyloid plaque<br/>accumulation"]
    S --> U["Neuronal dysfunction<br/>and cognitive decline"]
    T --> U

    classDef normal fill:#4fc3f7,stroke:#2196f3
    classDef therapeutic fill:#81c784,stroke:#4caf50
    classDef pathology fill:#ef5350,stroke:#f44336
    classDef outcome fill:#ffd54f,stroke:#ff9800
    classDef molecular fill:#ce93d8,stroke:#9c27b0

    class A,L pathology
    class B,C,D,E,F,G,H,I,J,M,N normal
    class K,O,P molecular
    class Q,R,S,T outcome
    class U pathology