Hypothesis Comparison

graph TD
    A["DNA damage and
oxidative stress
triggers"] -->|"activates"| B["p53/p21 and
p16INK4a/Rb
senescence pathways"]
    B -->|"induces"| C["Glial cell senescence
(microglia and astrocytes)"]
    C -->|"activates"| D["Senescence-Associated
Secretory Phenotype
(SASP)"]
    D -->|"upregulates"| E["NF-kappaB and
C/EBP-beta
transcription factors"]
    E -->|"transcriptionally
activates"| F["CD38 expression
(10-20 fold increase)"]
    F -->|"produces"| G["CD38 NAD+
glycohydrolase
enzyme activity"]
    G -->|"catalyzes"| H["NAD+ hydrolysis to
ADPR and
nicotinamide"]
    G -->|"synthesizes"| I["Cyclic ADPR
(cADP-ribose)
second messenger"]
    H -->|"creates"| J["Extracellular and
cytosolic NAD+
depletion zones"]
    J -->|"establishes"| K["Metabolic dead zones
(50-100 micrometer
radius)"]
    I -->|"mobilizes"| L["Intracellular
calcium release
signaling"]
    K -->|"compromises"| M["Neuronal
bioenergetic
integrity"]
    N["NAMPT salvage
pathway enzyme
activity"] -->|"competes with"| H
    N -->|"attempts"| O["NAD+ biosynthesis
from nicotinamide
recycling"]
    O -->|"insufficient
capacity"| J
    M -->|"leads to"| P["Mitochondrial
dysfunction and
ATP depletion"]
    L -->|"contributes to"| P
    P -->|"triggers"| Q["Neuronal death
and synaptic
dysfunction"]
    Q -->|"manifests as"| R["Progressive
neurodegeneration
phenotype"]
    S["CD38 inhibitors
and NAMPT
activators"] -->|"therapeutic
intervention"| G
    S -->|"restores"| T["NAD+ homeostasis
and neuronal
survival"]

    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,N,O molecular
    class J,K,L,M,P pathology
    class Q,R outcome
    class S,T therapeutic

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