Hypothesis Comparison

graph TD
    A["Pathological tau<br/>hyperphosphorylation<br/>(Ser202/Thr205, Thr231)"]
    B["Ubiquitinated tau<br/>species"]
    C["ESCRT-0 complex<br/>(HRS recognition)"]
    D["Early endosome<br/>formation"]
    E["ESCRT-I/II<br/>recruitment"]
    F["CHMP4B<br/>(ESCRT-III core)"]
    G["CHMP2A/CHMP3/CHMP6<br/>co-assembly"]
    H["Membrane scission<br/>and ILV formation"]
    I["VPS4A/VPS4B<br/>ATPase complex"]
    J["ESCRT-III<br/>disassembly"]
    K["MVB maturation"]
    L["Exosome release<br/>with tau cargo"]
    M["Extracellular tau<br/>propagation"]
    N["Neurodegeneration<br/>progression"]
    O["CHMP4B modulation<br/>therapeutic target"]

    A -->|"phosphorylation events"| B
    B -->|"substrate recognition"| C
    C -->|"endosomal sorting"| D
    D -->|"machinery recruitment"| E
    E -->|"ESCRT-III activation"| F
    F -->|"complex assembly"| G
    G -->|"membrane remodeling"| H
    H -->|"energy requirement"| I
    I -->|"ATP hydrolysis"| J
    J -->|"vesicle maturation"| K
    K -->|"cargo release"| L
    L -->|"intercellular transfer"| M
    M -->|"pathology spread"| N
    O -->|"therapeutic intervention"| F

    classDef normal fill:#4fc3f7
    classDef therapeutic fill:#81c784
    classDef pathology fill:#ef5350
    classDef outcome fill:#ffd54f
    classDef molecular fill:#ce93d8

    class D,E,G,H,I,J,K normal
    class O therapeutic
    class A,B,M,N pathology
    class L outcome
    class C,F molecular

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