Hypothesis Comparison

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

graph TD
    A["Cellular Stress and DNA Damage"]
    B["Astrocyte Senescence Induction"]
    C["SASP Activation"]
    D["Pro-inflammatory Cytokine Release"]
    E["TNF-alpha and IL-1beta Secretion"]
    F["NF-kappaB Pathway Activation"]
    G["AQP4 Polarity Loss"]
    H["Dystroglycan Complex Disruption"]
    I["Glymphatic System Dysfunction"]
    J["Amyloid-beta Accumulation"]
    K["Tau Protein Aggregation"]
    L["Neuroinflammation Amplification"]
    M["Neuronal Death"]
    N["Cognitive Decline"]
    O["Anti-SASP Therapy"]
    P["AQP4 Restoration"]

    A -->|"oxidative stress"| B
    B -->|"senescence markers"| C
    C -->|"inflammatory cascade"| D
    D -->|"cytokine production"| E
    E -->|"signaling activation"| F
    F -->|"transcriptional changes"| G
    G -->|"membrane disruption"| H
    H -->|"clearance impairment"| I
    I -->|"protein accumulation"| J
    I -->|"protein misfolding"| K
    J -->|"toxic aggregates"| L
    K -->|"neurofibrillary tangles"| L
    L -->|"cell death pathways"| M
    M -->|"functional loss"| N
    O -->|"senolytic treatment"| C
    O -->|"polarity rescue"| P

    subgraph INITIATION["Senescence Initiation"]
        A
        B
        C
    end

    subgraph SASP["SASP Cascade"]
        D
        E
        F
    end

    subgraph AQP4_DYSFUNCTION["AQP4 Dysfunction"]
        G
        H
        I
    end

    subgraph PATHOLOGY["Neurodegenerative Pathology"]
        J
        K
        L
        M
        N
    end

    subgraph THERAPY["Therapeutic Intervention"]
        O
        P
    end

    style A fill:#4fc3f7
    style B fill:#ef5350
    style C fill:#ef5350
    style D fill:#ef5350
    style E fill:#ef5350
    style F fill:#ef5350
    style G fill:#ef5350
    style H fill:#ef5350
    style I fill:#ef5350
    style J fill:#ef5350
    style K fill:#ef5350
    style L fill:#ef5350
    style M fill:#ef5350
    style N fill:#ffd54f
    style O fill:#81c784
    style P fill:#81c784