Hypothesis Comparison

graph TD
    A["Cellular Aging
Senescence Triggers"]
    B["Mitochondrial Dysfunction
Membrane Permeabilization"]
    C["PINK1/Parkin Pathway
Mitophagy Impairment"]
    D["ATG5/ATG7/LC3B
Autophagy Deficiency"]
    E["Cytoplasmic mtDNA
Accumulation"]
    F["Nuclear Envelope
Breakdown"]
    G["Cytoplasmic dsDNA
Recognition"]
    H["cGAS Activation
Conformational Change"]
    I["ATP and GTP
Substrate Binding"]
    J["cGAMP Synthesis
Second Messenger Production"]
    K["STING Activation
ER Translocation"]
    L["TBK1/IRF3
Phosphorylation Cascade"]
    M["Type I Interferon
Transcriptional Response"]
    N["Pro-inflammatory Cytokines
IL-1beta and TNF-alpha"]
    O["Microglial Activation
M1 Polarization"]
    P["Astrocyte Reactivity
A1 Phenotype"]
    Q["Neuroinflammation
Chronic Activation"]
    R["DNASE2 Deficiency
DNA Clearance Failure"]
    S["Neuronal Death
Synaptic Loss"]
    T["Neurodegeneration
Cognitive Decline"]

    A -->|"triggers"| B
    A -->|"impairs"| C
    A -->|"reduces"| D
    B -->|"releases"| E
    A -->|"causes"| F
    C -->|"fails to clear"| E
    D -->|"accumulates"| E
    F -->|"mixes with"| G
    E -->|"becomes"| G
    G -->|"binds to"| H
    H -->|"utilizes"| I
    I -->|"produces"| J
    J -->|"activates"| K
    K -->|"phosphorylates"| L
    L -->|"induces"| M
    L -->|"promotes"| N
    M -->|"activates"| O
    N -->|"polarizes"| O
    M -->|"induces"| P
    N -->|"activates"| P
    O -->|"drives"| Q
    P -->|"sustains"| Q
    E -->|"overwhelms"| R
    R -->|"perpetuates"| G
    Q -->|"causes"| S
    S -->|"leads to"| T

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

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