Hypothesis Comparison

graph TD
    A["Hypoxic Stress and Inflammation"]
    B["HIF-1alpha Activation"]
    C["PDK1 Upregulation"]
    D["PFKFB3 Induction"]
    E["LDHA Overexpression"]
    F["Pyruvate Dehydrogenase Inhibition"]
    G["Enhanced Glycolysis"]
    H["Lactate Accumulation"]
    I["OPC Metabolic Dysfunction"]
    J["Impaired OPC Differentiation"]
    K["Reduced Myelination"]
    L["Axonal Degeneration"]
    M["Cell-Specific PDK1 Inhibitors"]
    N["PFKFB3 Antagonists"]
    O["Metabolic Reprogramming Therapy"]
    P["Enhanced Myelin Repair"]

    A -->|"oxidative stress"| B
    B -->|"transcriptional activation"| C
    B -->|"glycolytic upregulation"| D
    B -->|"lactate production"| E
    C -->|"kinase activity"| F
    D -->|"rate-limiting enzyme"| G
    E -->|"metabolic flux"| H
    F -->|"mitochondrial dysfunction"| I
    G -->|"aerobic glycolysis"| I
    H -->|"pH imbalance"| I
    I -->|"energy deficit"| J
    J -->|"maturation block"| K
    K -->|"myelin loss"| L
    M -->|"targeted inhibition"| O
    N -->|"glycolytic modulation"| O
    O -->|"metabolic restoration"| P

    classDef mechanism fill:#4fc3f7
    classDef pathology fill:#ef5350
    classDef therapy fill:#81c784
    classDef outcome fill:#ffd54f

    class A,B,C,D,E,F,G,H mechanism
    class I,J,K,L pathology
    class M,N,O therapy
    class P outcome

graph TD
    A["Cellular Senescence<br/>Astrocytes and Microglia"] -->|"Triggers"| B["SASP Activation<br/>Senescence-Associated<br/>Secretory Phenotype"]
    B -->|"Secretes"| C["Pro-inflammatory<br/>Cytokines<br/>IL-1beta, TNF-alpha, IL-6"]
    B -->|"Releases"| D["Complement Initiators<br/>C1q, C3, C4"]
    B -->|"Produces"| E["Chemokines and<br/>Matrix Proteases<br/>CCL2, MMP3"]
    
    D -->|"Activates"| F["Classical Complement<br/>Pathway Initiation<br/>C1q-C1r-C1s Complex"]
    F -->|"Cleaves"| G["C4 and C2<br/>Formation of<br/>C3 Convertase C4b2a"]
    G -->|"Amplifies"| H["C3 Cleavage<br/>C3a and C3b<br/>Generation"]
    
    H -->|"Forms"| I["C5 Convertase<br/>C4b2a3b Complex<br/>Alternative Pathway Feed-in"]
    I -->|"Generates"| J["C5a Anaphylatoxin<br/>Microglial<br/>Chemotaxis Signal"]
    I -->|"Initiates"| K["Terminal Pathway<br/>C5b-9 Membrane<br/>Attack Complex"]
    
    H -->|"Opsonizes"| L["Synaptic Tagging<br/>C3b Deposition on<br/>Neuronal Synapses"]
    L -->|"Recognized by"| M["Microglial CR3<br/>Complement Receptor 3<br/>CD11b-CD18"]
    M -->|"Triggers"| N["Complement-Mediated<br/>Synaptic Pruning<br/>Phagocytosis"]
    
    J -->|"Activates"| O["Microglial Migration<br/>and Activation<br/>M1 Polarization"]
    O -->|"Enhances"| N
    C -->|"Amplifies"| O
    
    N -->|"Results in"| P["Progressive Synapse Loss<br/>Before Plaque Formation<br/>Early AD Pathology"]
    P -->|"Leads to"| Q["Cognitive Decline<br/>Memory Impairment<br/>Neurodegeneration"]
    
    R["Therapeutic C1q-C3<br/>Inhibition in SASP<br/>Microenvironments"] -->|"Blocks"| D
    R -->|"Prevents"| F
    
    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,B,C,D,E normal
    class F,G,H,I,J,K,L,M molecular
    class N,O,P pathology
    class Q outcome
    class R therapeutic