gene

SPP1

Entity Detail — Knowledge Graph Node

Understanding Entity Pages

This page aggregates everything SciDEX knows about SPP1: its mechanistic relationships (Knowledge Graph edges), hypotheses targeting it, analyses mentioning it, and supporting scientific papers. The interactive graph below shows its immediate neighbors. All content is AI-synthesized from peer-reviewed literature.

476Connections

28Hypotheses

5Analyses

50Outgoing

50Incoming

5Experiments

5Debates

Summary

SPP1 encodes osteopontin, a matricellular protein involved in neuroinflammation, cell survival, and neurodegenerative disease pathogenesis

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🧬 Gene Info

Gene Symbol	Secreted Phosphoprotein 1 (Osteopontin)
Chromosome	4q21.1
Function	encodes a secreted matricellular glycoprotein that functions as a cytokine, chemokine, and extracellular matrix protein.
Amino Acids	314 aa
Pathways	Amyloid, Angiogenesis, Apoptosis, Complement, Immune Response
UniProt ID	P08421
NCBI Gene ID	6696
Ensembl ID	ENSG00000118733
OMIM	166490
Associated Diseases	AD, aging/AD, Als, Alzheimer, Alzheimer's disease, Cancer
Known Drugs/Compounds	amyloid-beta oligomers, Bap, BaP, rapamycin, ursolic acid
Interactions	ABCA1, Actin, Akt, AKT, ALZHEIMER, ALZHEIMER'S DISEASE
SciDEX Hypotheses	Temporal SPP1 Inhibition During Critical Windows PDGF-BB/PDGFRβ/STAT3 Paracrine Signaling Axis Medi LRP1/NLRP3/IL-1β Cascade Links Aβ Endocytosis to I (+11 more)
KG Connections	476 knowledge graph edges
Databases	GeneCards HPA STRING

🔮 Predicted Structure: SPP1 — AlphaFold P08421 Click to expand

AI-predicted structure from AlphaFold | Powered by Mol*

Wiki Pages (3)

Knowledge base pages for this entity

Canonical Page

SPP1 Gene

gene · 1494 words

→

Validated Hypothesis: TREM2-Dependent Switch Hypothesis: TREM2 Agonism Redirects SPP1 Signaling from Destructive to Restorative

hypothesis · 4010 words

→

Osteopontin (SPP1)

protein · 2490 words

→

Pathway Diagram

graph TD
    SPP1["SPP1/Osteopontin
Matricellular Protein"] -->|"activates"| C1QA["C1QA/Complement"]
    SPP1 -->|"activates"| Complement["Complement System"]
    SPP1 -->|"activates"| GRN["GRN/Progranulin"]
    SPP1 -->|"activates"| CTSB["CTSB"]
    SPP1 -->|"activates"| Amyloid["Amyloid Pathology"]

    SPP1 -->|"inhibits"| Angiogenesis["Angiogenesis"]
    SPP1 -->|"expressed in"| Myeloid["Myeloid Cells"]

    CHI3L1["CHI3L1"] -->|"regulates"| SPP1
    GBM["GBM"] -->|"activates"| SPP1
    ICAM1["ICAM1"] -->|"inhibits"| SPP1
    MMP9["MMP9"] -->|"inhibits"| SPP1

    SPP1 -->|"implicated in"| AD["Alzheimer's Disease"]
    SPP1 -->|"implicated in"| ALS["ALS"]
    SPP1 -->|"activates"| Dementia["Dementia"]
    SPP1 -->|"regulates"| Glioblastoma["Glioblastoma"]
    SPP1 -->|"therapeutic target"| Inflammation["Neuroinflammation"]

    style SPP1 fill:#e74c3c,stroke:#c0392b,color:#e0e0e0
    style C1QA fill:#3498db,stroke:#2980b9,color:#e0e0e0
    style Complement fill:#3498db,stroke:#2980b9,color:#e0e0e0
    style AD fill:#9b59b6,stroke:#8e44ad,color:#e0e0e0
    style ALS fill:#9b59b6,stroke:#8e44ad,color:#e0e0e0
    style Inflammation fill:#f39c12,stroke:#e67e22,color:#e0e0e0

Outgoing (296)

Target	Relation	Type	Str
microglial phagocytosis	drives	process	0.95
SYNAPTIC ENGULFMENT	mediates	entity	0.95
Atherosclerosis	contributes_to	disease	0.95
Microglial Phagocytic States	associated_with	process	0.95
Th17 cell differentiation	promotes	process	0.95
Microglial Phagocytosis	activates	process	0.95
Synaptic Engulfment	mediates	process	0.95
Macrophage Inflammation	promotes	process	0.95
Lipid Dysregulation	promotes	phenotype	0.95
Microglial Phagocytosis	promotes	process	0.95
PHAGOCYTOSIS	regulates	entity	0.95
ALZHEIMER'S DISEASE	implicated_in	entity	0.95
ALZHEIMER'S DISEASE	involved_in	disease	0.95
ITGB1	binds_to	protein	0.93
microglial phagocytic state	associated_with	phenotype	0.93
CD44	binds_to	protein	0.93
Microglia	associated_with	cell_type	0.92
synaptic engulfment	promotes	process	0.92
ERK	activates	protein	0.92
MICROGLIA	mediates	cell_type	0.90
Synaptic Loss	contributes_to	phenotype	0.90
Phagocytic Markers	upregulates	biomarker	0.90
HIPPOCAMPUS	expressed_in	entity	0.90
ITGAV	binds_to	protein	0.90
C1Q	upregulates	entity	0.90
microglial_activation	activates	process	0.90
Inflammation	promotes	process	0.90
macrophage inflammation	promotes	process	0.90
microglia	induces	cell_type	0.90
GRN	upregulates	gene	0.90
CTSB	upregulates	gene	0.90
PI3K/Akt/mTOR pathway	activates	pathway	0.90
NSCLC	causes	disease	0.90
C1QA	upregulates	gene	0.90
idiopathic pulmonary fibrosis	causes	disease	0.90
Alzheimer's Disease	therapeutic_target	disease	0.88
Microglial Phagocytosis	upregulates	process	0.88
Macrophage Cytotoxicity	mediates	phenotype	0.85
Alzheimer'S Disease	involved_in	disease	0.85
lipid dysregulation	mediates	phenotype	0.85
foam cell phenotype	promotes	phenotype	0.80
phagocytic_state	induces	process	0.80
MICROGLIA	associated_with	cell_type	0.80
atherosclerosis	therapeutic_target	disease	0.80
CD36	upregulates	gene	0.75
PLIN2	upregulates	gene	0.75
ABCA1	suppresses	gene	0.75
Senescence	activates	disease	0.75
C3 expression	upregulates	protein	0.70
Synapse Engulfment	causes	phenotype	0.70

Incoming (180)

Source	Relation	Type	Str
h-immunity-03dc171e	relates_to	hypothesis	0.00
BaP	upregulates	compound	0.95
PERIVASCULAR MACROPHAGES	expressed_in	entity	0.95
Mir-692	inhibits	biomarker	0.95
Bap	upregulates	compound	0.95
ursolic acid	inhibits	drug	0.91
Bap	binds	compound	0.90
PERIVASCULAR FIBROBLASTS	expressed_in	entity	0.90
Perivascular Macrophages	upregulates	cell_type	0.90
perivascular_cells	upregulates	cell_type	0.90
Perivascular Fibroblasts	upregulates	cell_type	0.85
BaP	binds	compound	0.85
Perivascular Cells	expressed_in	cell_type	0.85
amyloid-beta oligomers	modulates	compound	0.80
MICROGLIA	associated_with	cell_type	0.80
RPS18	co_expressed_with	gene	0.80
developmental synaptic pruning	associated_with	phenotype	0.70
Perivascular macrophages	regulates	cell_type	0.70
Aβ oligomers	causes	protein	0.70
Perivascular macrophages	associated_with	cell_type	0.70
perivascular_macrophages	regulates	cell_type	0.70
IMMUNE INFILTRATION	expressed_in	gene	0.60
C1QA	activates	gene	0.60
CHI3L1	regulates	gene	0.60
GBM	activates	gene	0.60
STAT3	regulates	gene	0.60
GBM	associated_with	gene	0.60
YAP1	associated_with	gene	0.60
BLM	activates	gene	0.60
AKT	activates	gene	0.60
CD36	activates	gene	0.60
PLIN2	activates	gene	0.60
CSF1R	activates	gene	0.60
GENES	associated_with	gene	0.60
ZBTB20	associated_with	gene	0.60
ANK3	associated_with	gene	0.60
ANK3	therapeutic_target	gene	0.60
ETV6	therapeutic_target	gene	0.60
ERK	associated_with	gene	0.60
CANCER	therapeutic_target	gene	0.60
JAK	associated_with	gene	0.60
APOPTOSIS	associated_with	gene	0.60
CTSB	activates	gene	0.60
CHONDROCYTE APOPTOSIS	expressed_in	gene	0.60
APOPTOSIS	expressed_in	gene	0.60
COMPLEMENT	activates	gene	0.60
AMYLOID	activates	gene	0.60
ALZHEIMER'S DISEASE	activates	gene	0.60
APOPTOSIS	activates	gene	0.60
ROS	activates	gene	0.60

Targeting Hypotheses (28)

Hypotheses where this entity is a therapeutic target

Hypothesis	Score	Disease	Analysis
TREM2-Dependent Switch Hypothesis: TREM2 Agonism Redirects S	0.813	synaptic-biology	Does SPP1-mediated synaptic engulfment r
Temporal SPP1 Inhibition During Critical Windows	0.752	neuroinflammation	What molecular mechanisms mediate SPP1-i
SPP1+ DAM as Source of Autoimmunity in Neurodegeneration	0.660	alzheimers	-
Metabolic Rewiring via SPP1-Induced HIF1α Glycolytic Shift	0.620	neuroinflammation	What molecular mechanisms mediate SPP1-i
PDGF-BB/PDGFRβ/STAT3 Paracrine Signaling Axis Mediates Aβ-In	0.618	neurodegeneration	How do perivascular cells specifically r

Complement Cascade Specificity: Microglial C3aR Antagonism D	0.618	synaptic-biology	Does SPP1-mediated synaptic engulfment r
LRP1/NLRP3/IL-1β Cascade Links Aβ Endocytosis to Inflammasom	0.617	neurodegeneration	How do perivascular cells specifically r
Temporal NLRP3 Inhibition During SPP1-Driven Microglial Acti	0.551	neuroinflammation	What molecular mechanisms mediate SPP1-i
Astrocytic SPP1 Modulation Through STAT3-Dependent Transcrip	0.551	neuroinflammation	What molecular mechanisms mediate SPP1-i
Synaptic Vulnerability Window Temporal Targeting: Transient	0.536	synaptic-biology	Does SPP1-mediated synaptic engulfment r
CD36 Acts as Primary Aβ Oligomer Sensor on Perivascular Macr	0.535	neurodegeneration	How do perivascular cells specifically r
CD33-Dependent Switch Hypothesis: CD33 Antagonism Redirects	0.519	synaptic-biology	Does SPP1-mediated synaptic engulfment r
Stage-Dependent Biphasic SPP1 Targeting: Early Enhancement F	0.503	synaptic-biology	Does SPP1-mediated synaptic engulfment r
TREM2 on Perivascular Macrophages Senses Aβ and Drives SPP1	0.496	neurodegeneration	How do perivascular cells specifically r
Temporal NLRP3 Inhibition via SPP1-Mediated Mitophagy Enhanc	0.496	neuroinflammation	What molecular mechanisms mediate SPP1-i
YAP/TAZ Mechanosensing Cooperates with NF-κB to Amplify SPP1	0.492	neurodegeneration	How do perivascular cells specifically r
Astrocytic SPP1 Modulation via STAT3-Dependent Transcription	0.459	neuroinflammation	What molecular mechanisms mediate SPP1-i
Mitochondrial Damage-Triggered SPP1 Inflammasome Coupling	0.453	neuroinflammation	What molecular mechanisms mediate SPP1-i
Astrocytic SPP1 Modulation for Neuroinflammatory Resolution	0.447	neuroinflammation	What molecular mechanisms mediate SPP1-i
RAGE/STAT3/IL-6 Autocrine Loop Mediates Aβ-Induced SPP1 Upre	0.442	neurodegeneration	How do perivascular cells specifically r
Source-Specific SPP1 Inhibition: Perivascular Cell Targeting	0.429	synaptic-biology	Does SPP1-mediated synaptic engulfment r
P2X7/P2Y12 Purinergic Signaling Connects Aβ Aggregation to S	0.423	neurodegeneration	How do perivascular cells specifically r
Partial Agonist/SPP1 Splice Variant Strategy: Splice-Switchi	0.311	synaptic-biology	Does SPP1-mediated synaptic engulfment r
CD44-SPP1 Axis Precision Targeting	0.000	-	What molecular mechanisms mediate SPP1-i
Complement-Independent SPP1 Signaling Disruption	0.000	-	What molecular mechanisms mediate SPP1-i
Metabolic Reprogramming of SPP1-Activated Microglia	0.000	-	What molecular mechanisms mediate SPP1-i
Epigenetic Silencing of SPP1 in Disease-Associated Microglia	0.000	-	What molecular mechanisms mediate SPP1-i
SPP1-Integrin Competitive Inhibition	0.000	-	What molecular mechanisms mediate SPP1-i

Mentioning Analyses (5)

Scientific analyses that reference this entity

What molecular mechanisms mediate SPP1-induced microglial phagocytic activation

neuroinflammation | 2026-04-15 | 13 hypotheses Top: 0.752

Does SPP1-mediated synaptic engulfment represent beneficial clearance or patholo

synaptic biology | 2026-04-07 | 8 hypotheses Top: 0.813

How do perivascular cells specifically recognize and respond to amyloid-β to upr

neurodegeneration | 2026-04-06 | 7 hypotheses Top: 0.618

What molecular mechanisms mediate SPP1-induced microglial phagocytic activation

neuroinflammation | 2026-04-06 | 7 hypotheses Top: 0.761

Immune atlas neuroinflammation analysis in neurodegeneration

Neuroinflammation | 2026-04-03 | 14 hypotheses Top: 0.681

Experiments (5)

Experimental studies targeting or related to this entity

Experiment	Type	Disease	Score	Model	Status	Est. Cost
SPP1-mediated microglial synaptic engulfment assay	exploratory	Alzheimer's disease	0.950	AD mouse models with amyloid-β	proposed	N/A
SPP1 upregulation in perivascular cells in AD mouse models	exploratory	Alzheimer's disease	0.900	AD mouse models	proposed	N/A
Spp1 knockout prevents synaptic loss in AD mouse models	validation	Alzheimer's disease	0.900	Spp1 knockout AD mouse models	proposed	N/A
Single-cell RNA sequencing of microglial states in AD hippocampus	exploratory	Alzheimer's disease	0.850	AD mouse hippocampus	proposed	N/A
Cell-cell interaction analysis of perivascular-microglial crosstalk	exploratory	Alzheimer's disease	0.800	AD mouse models	proposed	N/A

Related Papers (5)

Scientific publications cited in analyses involving this entity

Title & PMID	Authors	Journal	Year	Citations
Perivascular cells induce microglial phagocytic states and synaptic engulfment v [PMID:36747024]	De Schepper S, Ge JZ, Sierksma A, Crowle	Nat Neurosci	2023	2
A CRISPRi/a platform in human iPSC-derived microglia uncovers regulators of dise [PMID:35953545]	["Dr\u00e4ger Nina M", "Sattler Sydney M	Nature neuroscience	2022	0
Regulating microglial miR-155 transcriptional phenotype alleviates Alzheimer's-i [PMID:36076283]	Shi H, Yin Z, Koronyo Y, Fuchs DT, Sheyn	Acta neuropathologica communic	2022	0
Anti-human TREM2 induces microglia proliferation and reduces pathology in an Alz [PMID:32579671]	Wang S, Mustafa M, Yuede CM, Salazar SV,	The Journal of experimental me	2020	0
Anti-human TREM2 induces microglia proliferation and reduces pathology in an Alz [PMID:32579671]	Wang S, Mustafa M, Yuede CM, Salazar SV,	J Exp Med	2020	0

Debates (5)

Multi-agent debates referencing this entity

The study shows SPP1 from perivascular cells drives microglial synaptic engulfme

closed · Rounds: 4 · Score: 0.70 · 2026-04-22

The abstract indicates SPP1 upregulation occurs in perivascular macrophages and

closed · Rounds: 4 · Score: 0.67 · 2026-04-22

While SPP1 absence prevents synaptic loss, it's unclear whether this represents

closed · Rounds: 4 · Score: 0.69 · 2026-04-21

What molecular mechanisms mediate SPP1-induced microglial phagocytic activation

closed · Rounds: 5 · Score: 0.95 · 2026-04-15

Comprehensive analysis of immune cell subtypes in neurodegeneration: microglia s

closed · Rounds: 4 · Score: 0.85 · 2026-04-03

Related Research

Hypotheses and analyses mentioning SPP1 in their description or question text

Complement Cascade Specificity: Microglial C3aR Antagonism Downstream of SPP1

Score: 0.618 · synaptic-biology · 2026-04-21

## Mechanistic Overview Complement Cascade Specificity: Microglial C3aR Antagonism Downstream of SPP1 starts from the cl

LRP1/NLRP3/IL-1β Cascade Links Aβ Endocytosis to Inflammasome Activation and SPP

Score: 0.617 · neurodegeneration · 2026-04-22

**Molecular Mechanism and Rationale** The proposed LRP1/NLRP3/IL-1β cascade represents a critical mechanistic link betw

Temporal NLRP3 Inhibition During SPP1-Driven Microglial Activation Windows

Score: 0.551 · neuroinflammation · 2026-04-20

## Mechanistic Overview Temporal NLRP3 Inhibition During SPP1-Driven Microglial Activation Windows starts from the claim

Astrocytic SPP1 Modulation Through STAT3-Dependent Transcriptional Control

Score: 0.551 · neuroinflammation · 2026-04-20

## Mechanistic Overview Astrocytic SPP1 Modulation Through STAT3-Dependent Transcriptional Control starts from the claim

Synaptic Vulnerability Window Temporal Targeting: Transient SPP1 Blockade

Score: 0.536 · synaptic-biology · 2026-04-21

## Mechanistic Overview Synaptic Vulnerability Window Temporal Targeting: Transient SPP1 Blockade starts from the claim

CD36 Acts as Primary Aβ Oligomer Sensor on Perivascular Macrophages, Triggering

Score: 0.535 · neurodegeneration · 2026-04-22

## Mechanistic Overview CD36 Acts as Primary Aβ Oligomer Sensor on Perivascular Macrophages, Triggering NF-κB-Dependent

CD33-Dependent Switch Hypothesis: CD33 Antagonism Redirects SPP1 Signaling from

Score: 0.519 · synaptic-biology · 2026-04-26

CD33 overactivation shifts SPP1-mediated microglial response from restorative (disease-associated microglia pathway) to

Stage-Dependent Biphasic SPP1 Targeting: Early Enhancement Followed by Late Inhi

Score: 0.503 · synaptic-biology · 2026-04-21

## Mechanistic Overview Stage-Dependent Biphasic SPP1 Targeting: Early Enhancement Followed by Late Inhibition starts fr

TREM2 on Perivascular Macrophages Senses Aβ and Drives SPP1 Upregulation Through

Score: 0.496 · neurodegeneration · 2026-04-22

## Mechanistic Overview TREM2 on Perivascular Macrophages Senses Aβ and Drives SPP1 Upregulation Through CSF1R-Mediated

Temporal NLRP3 Inhibition via SPP1-Mediated Mitophagy Enhancement During Critica

Score: 0.496 · neuroinflammation · 2026-04-21

## Mechanistic Overview Temporal NLRP3 Inhibition via SPP1-Mediated Mitophagy Enhancement During Critical Neuroinflammat

YAP/TAZ Mechanosensing Cooperates with NF-κB to Amplify SPP1 Transcription in Pe

Score: 0.492 · neurodegeneration · 2026-04-22

## Mechanistic Overview YAP/TAZ Mechanosensing Cooperates with NF-κB to Amplify SPP1 Transcription in Perivascular Fibro

Astrocytic SPP1 Modulation via STAT3-Dependent Transcriptional Control

Score: 0.459 · neuroinflammation · 2026-04-21

## Mechanistic Overview Astrocytic SPP1 Modulation via STAT3-Dependent Transcriptional Control starts from the claim tha

Mitochondrial Damage-Triggered SPP1 Inflammasome Coupling

Score: 0.453 · neuroinflammation · 2026-04-21

## Mechanistic Overview Mitochondrial Damage-Triggered SPP1 Inflammasome Coupling starts from the claim that modulating

Astrocytic SPP1 Modulation for Neuroinflammatory Resolution

Score: 0.447 · neuroinflammation · 2026-04-21

## Mechanistic Overview Astrocytic SPP1 Modulation for Neuroinflammatory Resolution starts from the claim that modulatin

RAGE/STAT3/IL-6 Autocrine Loop Mediates Aβ-Induced SPP1 Upregulation in Perivasc

Score: 0.442 · neurodegeneration · 2026-04-22

## Mechanistic Overview RAGE/STAT3/IL-6 Autocrine Loop Mediates Aβ-Induced SPP1 Upregulation in Perivascular Fibroblasts