Microglia-Neuron Metabolic Cross-Talk in Neurodegeneration

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Microglia-Neuron Metabolic Cross-Talk in Neurodegeneration

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Microglia-Neuron Metabolic Cross-Talk in Neurodegeneration

Overview

[Microglia](/cell-types/microglia-neuroinflammation), the resident immune cells of the central nervous system, engage in bidirectional metabolic communication with [neurons](/entities/neurons) that is essential for brain homeostasis. This metabolic cross-talk becomes dysregulated in neurodegenerative diseases including Alzheimer's disease (AD), [Parkinson's disease (PD)](/diseases/parkinsons-disease), and [amyotrophic lateral sclerosis (ALS)](/diseases/amyotrophic-lateral-sclerosis). Understanding this axis reveals critical mechanisms of neuroinflammation and identifies novel therapeutic targets for neuroprotection[@heneka2015][@glass2010].

The brain represents approximately 2% of body weight yet consumes about 20% of resting metabolic energy, with neurons being particularly energy-demanding due to their constant ionic pumping and synaptic activity[@mergenthaler2013]. Microglia, while comprising only 10-15% of brain cells, play crucial metabolic support roles that become compromised in neurodegeneration.

Metabolic Functions of Microglia

Energy Metabolism

Microglia exhibit distinct metabolic profiles compared to neurons and other glial cells:

...

Microglia-Neuron Metabolic Cross-Talk in Neurodegeneration

Overview

[Microglia](/cell-types/microglia-neuroinflammation), the resident immune cells of the central nervous system, engage in bidirectional metabolic communication with [neurons](/entities/neurons) that is essential for brain homeostasis. This metabolic cross-talk becomes dysregulated in neurodegenerative diseases including Alzheimer's disease (AD), [Parkinson's disease (PD)](/diseases/parkinsons-disease), and [amyotrophic lateral sclerosis (ALS)](/diseases/amyotrophic-lateral-sclerosis). Understanding this axis reveals critical mechanisms of neuroinflammation and identifies novel therapeutic targets for neuroprotection[@heneka2015][@glass2010].

The brain represents approximately 2% of body weight yet consumes about 20% of resting metabolic energy, with neurons being particularly energy-demanding due to their constant ionic pumping and synaptic activity[@mergenthaler2013]. Microglia, while comprising only 10-15% of brain cells, play crucial metabolic support roles that become compromised in neurodegeneration.

Metabolic Functions of Microglia

Energy Metabolism

Microglia exhibit distinct metabolic profiles compared to neurons and other glial cells:

Glycolytic bias: Resting microglia rely primarily on glycolysis for energy production, allowing rapid activation when needed[@volgi2024]
Oxidative phosphorylation: Activated microglia shift toward OXPHOS under certain conditions, particularly when engaging in prolonged phagocytosis
Ketone utilization: Microglia can metabolize ketone bodies as an alternative fuel, becoming more important during aging or fasting[@jain2023]
Lipid metabolism: Critical for inflammatory responses and phagocytosis, with altered lipid metabolism implicated in neurodegenerative diseases

Mermaid diagram (expand to render)

Metabolic Support to Neurons

Microglia provide indirect metabolic support to neurons through multiple mechanisms:

Lactate shuttle: Microglia export lactate that may contribute to neuronal energy needs, particularly during increased neuronal activity[@pellerin2021]

Growth factor production: BDNF and other neurotrophic factors support neuronal metabolism and survival

Ion homeostasis: Buffering of extracellular potassium during neuronal firing

Waste clearance: Phagocytosis of debris reduces inflammatory burden that would otherwise impair neuronal metabolism

Neuron-Derived Metabolic Signals

ATP and Adenosine

Neuronal activity releases ATP that activates microglia through purinergic signaling:

P2X receptors: Ionotropic ATP receptors (P2X4, P2X7) that respond to extracellular ATP[@burnstock2019]
P2Y receptors: Metabotropic ATP receptors (P2Y12) involved in microglial process extension
A1 receptors: Adenosine receptors mediating anti-inflammatory signals that limit microglial activation

The ATP-adenosine axis creates a feedback loop where neuronal activity modulates microglial surveillance, creating a homeostatic system where more active neurons attract greater microglial attention[@netter2020].

Fractalkine Signaling

The CX3CL1-CX3CR1 pathway provides neuron-to-microglia communication:

CX3CL1 (Fractalkine): Expressed on neurons, released in soluble form or membrane-bound
CX3CR1: Expressed exclusively on microglia in the CNS

This signaling maintains microglia in a surveillance state and limits harmful inflammation[@pawelec2020]. Deficiency in CX3CR1 leads to increased microglial activation and neurotoxicity in multiple models.

Dysfunction in Neurodegeneration

Alzheimer's Disease

In AD, microglia-neuron metabolic cross-talk is disrupted through multiple mechanisms:

[TREM2](/proteins/trem2) variants: Risk variants (R47H, R62H) impair microglial metabolic functions, including lipid metabolism and phagocytosis[@ulland2020]
[Amyloid-beta](/proteins/amyloid-beta) phagocytosis: Metabolic burden overwhelms microglial capacity, leading to cellular stress
Lactate dysregulation: Altered lactate shuttling affects neuronal function and contributes to network hyperexcitability
Chronic inflammation: Pro-inflammatory state consumes metabolic resources and impairs supportive functions

Research shows TREM2 deficiency impairs microglial metabolic adaptation to Aβ pathology, with reduced ability to metabolize lipids and support neuronal energy needs[@zhou2024]. Single-cell studies have identified disease-associated microglia (DAM) that upregulate lipid metabolism genes, but this response is blunted in TREM2 risk variant carriers.

Parkinson's Disease

Microglial dysfunction in PD includes several metabolic and inflammatory components:

[α-Synuclein](/proteins/alpha-synuclein) recognition: Chronic activation by extracellular α-synuclein leads to sustained inflammatory responses[@cookson2022]
Metabolic reprogramming: Warburg-like shift in microglial metabolism toward glycolysis even in resting conditions
Dopaminergic neuron support: Failure to provide trophic metabolic support contributes to neuronal vulnerability
Neuroinflammation: Sustained inflammatory response depletes energy reserves and produces neurotoxic metabolites

PET studies reveal increased microglial activation in PD substantia nigra correlating with motor severity[@gerhard2006]. Genetic studies have identified microglial genes (including [GBA](/genes/gba) and [LRRK2](/genes/lrrk2)) as PD risk factors, highlighting the importance of microglial function in disease pathogenesis.

Amyotrophic Lateral Sclerosis

In ALS, microglia contribute to motor neuron injury through metabolic dysfunction:

Excitotoxicity modulation: Altered glutamate metabolism affects excitotoxic stress on motor neurons
Metabolic competition: May limit neuronal access to metabolic substrates in the extracellular space
Oxidative stress: [Reactive oxygen species](/entities/reactive-oxygen-species) production from activated microglia
Trophic factor dysregulation: Altered BDNF/IGF-1 secretion affects neuronal survival

Studies in SOD1 mouse models show that microglial activation precedes motor neuron degeneration, with a progressive shift from neuroprotective to neurotoxic phenotypes[@boillee2006].

Therapeutic Implications

Targeting Microglial Metabolism

TREM2 modulators: Enhance microglial metabolic fitness and phagocytic capacity[@wang2024]

P2X7 antagonists: Reduce harmful purinergic signaling that drives chronic activation

Ketogenic interventions: Provide alternative metabolic substrates that reduce glycolytic burden

Metabolic antioxidants: Reduce oxidative stress burden on microglial mitochondria

Emerging Approaches

| Approach | Target | Development Status |
|----------|--------|-------------------|
| TREM2 agonism | TREM2 | Preclinical |
| P2X7 blockade | P2X7 receptor | Phase II trials |
| Ketone supplementation | Metabolic support | Clinical trials |
| Fractalkine analogs | CX3CR1 | Research phase |

Clinical Translation

Several strategies are being explored clinically:

CSF1R antagonists to modulate microglial density and activation
TREM2 antibodies to enhance receptor signaling
Minocycline as a broad microglial inhibitor (mixed results in clinical trials)
Microglial replacement therapies using bone marrow transplantation

Cross-References

[Microglia in Neurodegeneration](/cell-types/microglia-neuroinflammation)
[Neuroinflammation Pathway](/mechanisms/neuroinflammation-pathway)
[TREM2 Signaling in Neurodegeneration](/mechanisms/trem2-signaling)
[Alzheimer's Disease Mechanisms](/mechanisms/ad-biomarker-mechanism-map)
[Parkinson's Disease Mechanisms](/mechanisms/biomarkers-parkinsons)
[Metabolic Dysfunction in Alzheimer's](/mechanisms/metabolic-dysfunction-alzheimers)

External Links

[PubMed](https://pubmed.ncbi.nlm.nih.gov/)
[KEGG Pathways](https://www.genome.jp/kegg/pathway.html)

Metabolic coupling represents an emerging paradigm in understanding neuron-glia interactions. Recent single-cell transcriptomic studies have revealed microglial metabolic heterogeneity that correlates with brain regional vulnerability in neurodegenerative diseases.

Metabolic Heterogeneity in Disease

Single-nucleus RNA sequencing has identified distinct microglial metabolic states:

Disease-Associated Microglia (DAM): Upregulate lipid metabolism genes including APOE, TREM2-dependent pathways

Aging-associated microglia: Show mitochondrial dysfunction signatures

Region-specific microglia: Metabolism varies by brain region, explaining differential vulnerability

Mitochondrial Function in Microglia

Microglial mitochondria serve multiple functions beyond energy production:

ROS generation: Regulates inflammatory signaling through redox-sensitive pathways
Calcium handling: Mitochondrial calcium influences activation state
Apoptosis regulation: Mitochondrial permeability transition affects survival
Metabolic sensing: AMPK activation responds to cellular energy status

Therapeutic Implications

Metabolic Modulation Strategies

| Strategy | Target | Mechanism |
|----------|--------|----------|
| TREM2 agonism | Lipid metabolism | Enhance phagocytosis, metabolic fitness |
| CSF1R inhibition | Microglial proliferation | Reduce microglial burden |
| P2X7 blockade | Purinergic signaling | Reduce chronic activation |
| Ketogenic diet | Alternative metabolism | Provide ketone substrates |

Clinical Trials

TREM2 antibodies (e.g., AZD0323): Phase II/III trials for AD
CSF1R inhibitors (e.g., PLX3397): Tested in AD and ALS
Minocycline: Mixed results in PD and ALS trials
NAC: Ongoing trials for ALS and PD cognitive dysfunction

Future Directions

Understanding microglial metabolism offers the opportunity to develop disease-modifying therapies that work by enhancing the brain's endogenous neuroprotective mechanisms rather than simply reducing inflammation.

Historical Context

The appreciation of microglial metabolic functions has evolved significantly:

1900s: Microglia recognized as brain immune cells
1980s: Discovery of resting and activated states
2000s: Fractalkine pathway identified
2010s: TREM2 genetics reveal microglial role in AD
2020s: Single-cell metabolism becomes tractable

Conclusion

Microglia-neuron metabolic cross-talk represents a fundamental axis of brain homeostasis that becomes disrupted in all major neurodegenerative diseases. The metabolic support functions of microglia, including lactate shuttle, trophic factor release, and waste clearance, are essential for neuronal survival. Targeting microglial metabolism offers a promising therapeutic approach that may restore supportive functions while reducing harmful inflammation.

Neuroimmune Interactions

Pattern Recognition Receptors

Microglia express multiple pattern recognition receptors (PRRs) that detect endogenous danger signals:

TLRs (Toll-like receptors): TLR2, TLR4 recognize Aβ, α-synuclein
NLRs (NOD-like receptors): NLRP3 inflammasome activation
RIG-I-like receptors: Detect nucleic acids from cellular damage
cGAS-STING pathway: Responds to cytosolic DNA

Inflammasome Activation

The NLRP3 inflammasome represents a key inflammatory pathway:

Activation triggers: Aβ, α-synuclein, ATP, ROS
Caspase-1 activation: Pro-IL-1β, IL-18 cleavage
Pyroptosis induction: Inflammatory cell death
Therapeutic targeting: NLRP3 inhibitors in development

Cytokine Networks

Microglial cytokines orchestrate neuroinflammation:

| Cytokine | Effect | Therapeutic Target |
|----------|--------|-------------------|
| IL-1β | Pro-inflammatory | Anakinra, Canakinumab |
| IL-6 | Pro-inflammatory | Tocilizumab |
| TNF-α | Pro-inflammatory | Etanercept, Infliximab |
| IL-10 | Anti-inflammatory | Gene therapy |
| TGF-β | Anti-inflammatory | None yet |

Region-Specific Microglial Function

Vulnerable Regions

Different brain regions show varying microglial responses:

Substantia nigra: High baseline activation, vulnerable to PD
Hippocampus: Strong Aβ response in AD
Motor cortex: Active in ALS progression
Cerebellum: Relatively spared in many disorders

Regional Transcriptomic Signatures

Single-cell studies reveal region-specific microglia:

Transcriptional profiles: Distinct by brain region
Aging effects: Vary regionally
Disease signatures: Region-specific DAM programs

Microglia in Normal Brain Function

Surveillance and Scanning

Resting microglia continuously scan their environment:

Process motility: 1-2 μm/minute process extension
Territory: ~30 μm diameter territory
Calcium signaling: Activity-dependent calcium transients
Neuronal interaction: Direct contact with synapses

Synapse Elimination

Microglia prune synapses during development and disease:

Complement system: C1q, C3标记 unwanted synapses
Phagocytic receptors: MEGF10, MERTK mediate engulfment
Activity-dependent: More active synapses less pruned
Disease dysregulation: Excessive or insufficient pruning

Research Tools and Models

Animal Models

| Model | Use | Limitations |
|-------|-----|-------------|
| CX3CR1-GFP | Visualization | Knockout phenotypes |
| TREM2 KO | TREM2 function | Developmental compensation |
| CSF1R antagonist | Depletion | Non-specific effects |
| Humanized mice | Human microglia | Limited replication |

Imaging Techniques

Two-photon microscopy: Live brain imaging
Light sheet: Large volume imaging
Super-resolution: Nanoscale structure
Single-cell RNAseq: Transcriptomic profiling

In Vitro Models

iPSC-derived microglia: Human disease modeling
Organoids: Brain organoid systems
Microfluidics: Controlled microenvironment
Co-cultures: Neuron-microglia interaction

Conclusions

The microglia-neuron metabolic cross-talk represents a fundamental axis of brain homeostasis that is disrupted in all major neurodegenerative diseases. The metabolic support functions of microglia, including lactate shuttle, trophic factor release, and waste clearance, are essential for neuronal survival. Understanding and targeting microglial metabolism offers a promising therapeutic approach that may restore supportive functions while reducing harmful inflammation.

Key takeaways:

Metabolic coupling between microglia and neurons is essential for brain function

TREM2 and other microglial receptors link metabolism to immune function

Therapeutic targeting of microglial metabolism is in active development

Region-specific vulnerability relates to microglial heterogeneity

Translational challenges remain but clinical trials are ongoing

Advanced Therapeutic Strategies

TREM2-Targeting Approaches

TREM2 represents one of the most promising therapeutic targets in neurodegeneration[@heneka2015]

TREM2 Agonists

Antibody-based activation: AL002c, JNJ-0856
Small molecule activators: In development
Gene therapy: AAV-TREM2 delivery
Mechanism: Enhances phagocytosis, lipid metabolism

TREM2 Biology

TREM2 (Triggering Receptor Expressed on Myeloid Cells 2) is a transmembrane receptor:

Expression: Limited to microglia in CNS
Ligands: Lipids, Aβ, ApoE
Signaling: DAP12 adaptor protein
Variants: R47H, R62H increase AD risk

CSF1R-Targeting Strategies

Colony-Stimulating Factor 1 Receptor controls microglial survival:

Antagonists

PLX3397 (Pexidartinib): Approved for tenosynovial giant cell tumor
PLX5622: Research tool, microglial depletion
ARW-791: Selective antagonist

Clinical Applications

AD trials: Mixed results
ALS trials: Safety established
PD trials: Ongoing

CX3CR1 Modulation

The fractalkine receptor offers neuroprotection potential:

Agonists

CX3CL1 derivatives: Recombinant protein
Small molecules: In development
Gene therapy: AAV delivery

Effects

Anti-inflammatory: Reduces cytokine production
Neuroprotective: Protects dopaminergic neurons
Cognitive benefit: Shown in AD models

Microglial Heterogeneity

Single-Cell Perspectives

Modern techniques reveal microglial diversity:

| Microglial Type | Markers | Function |
|----------------|---------|----------|
| Homeostatic | P2ry12, Cx3cr1 | Surveillance |
| DAM | Apoe, Tyrobp | Disease response |
| Age-associated | Cst3, Lilrb4 | Aging |
| Region-specific | Variable | Regional function |

Brain Regional Variation

Different regions show distinct microglial signatures:

Hippocampus: High baseline plasticity, DAM induction
Substantia nigra: Constitutively higher activation
Cortex: Variable by layer
Cerebellum: Relatively less studied

Microglia and Neurogenesis

Adult Neurogenesis

Microglia regulate neural stem cell niches:

Subventricular zone: Continuous neurogenesis
Hippocampal dentate gyrus: Cognitive plasticity
Microglial pruning: Affects new neuron integration
Therapeutic implication: Potential for regeneration

In Neurodegeneration

Neurogenesis impaired: Reduced in AD, PD
Microglial role: May contribute to impairment
Therapeutic targeting: Enhancement strategies

Microglia and Blood-Brain Barrier

BBB Interactions

Microglia communicate with vascular cells:

Pericyte relationships: Regulate BBB integrity
Endothelial crosstalk: Maintain barrier function
Perivascular macrophages: Separate population

In Disease

BBB disruption: Early event in neurodegeneration
Microglial involvement: Contributes to dysfunction
Therapeutic challenge: Drug delivery

Metabolic Imaging

PET Tracers

| Target | Tracer | Application |
|--------|--------|--------------|
| TSPO | PK11195 | Microglial activation |
| TSPO | DPA-713 | Improved binding |
| P2X7 | ATP analog | In development |
| MAO-B | Deprenyl | Astrocyte/microglia |

MRI Approaches

DTI: White matter integrity
RS fMRI: Functional connectivity
ASL: Cerebral blood flow
MRS: Metabolic markers

Computational Models

In Silico Approaches

Network analysis: Systems biology
Machine learning: Pattern recognition
Integrative models: Multi-scale modeling
Personalized medicine: Individual predictions

Conclusion and Future Directions

The microglia-neuron metabolic axis represents a fundamental yet complex therapeutic target. Key insights:

Metabolic coupling between microglia and neurons is essential for brain homeostasis

TREM2 and other receptors link metabolic state to immune function

Regional heterogeneity explains differential vulnerability

Multiple therapeutic approaches are in clinical development

Biomarker development will enable patient selection

Future directions include:

Single-cell resolution for personalized approaches
Spatial transcriptomics for cellular interactions
Temporal dynamics understanding disease progression
Combination therapies targeting multiple pathways

References

Unknown (n.d.)

Microglia and Specific Proteinopathies

Tauopathies

In Alzheimer's disease and other tauopathies:

Microglial activation: Correlates with tau burden
Tau uptake: Microglia internalize tau
Propagation: May spread tau via exosomes
Therapeutic implications: Targeting tau-microglia axis

Synucleinopathies

In Parkinson's disease and related disorders:

α-Synuclein recognition: Via TLR2, TLR4, FcγR
Chronic activation: Leads to dysfunction
Exosomal release: May propagate pathology
Immune modulation: Therapeutic strategy

TDP-43 Proteinopathies

In ALS and frontotemporal dementia:

Microglial response: Less characterized than AD/PD
NLRP3 inflammasome: Activation in models
Therapeutic targeting: Developing understanding

Prion Diseases

Microglial role: Both protective and pathogenic
Phagocytic clearance: Important for surveillance
Chronic activation: Contributes to neurodegeneration

Microglia in Aging

Morphology: Enlarged cell bodies, shortened processes
Transcriptome: DAM-like signatures
Function: Reduced surveillance, increased baseline inflammation
Implication: Increases neurodegeneration susceptibility

Interventions

Rejuvenation strategies: Young microglia transplantation
Metabolic optimization: Improving function
Reducing inflammation: Anti-inflammatory approaches

Sex Differences in Microglia

Male vs Female

Baseline differences: Sex-specific microglial phenotypes
Disease susceptibility: Sex-biased prevalence
Therapeutic implications: Sex-specific dosing may be needed

Microglia and Sleep

Recent Discoveries

Sleep deprivation: Increases microglial phagocytosis
Sleep quality: Linked to microglial function
Implications: Sleep as therapeutic target

Technical Considerations

Study Limitations

Post-mortem tissue: Limited availability
Animal models: Species differences
In vitro systems: Lack full complexity
Human studies: Ethical constraints

Emerging Technologies

iPSC-microglia: Patient-specific models
Brain organoids: Complex systems
Spatial transcriptomics: Cellular resolution
Live imaging: Real-time monitoring

Summary

Microglia-neuron metabolic cross-talk is essential for brain health and becomes dysregulated in all neurodegenerative diseases. Understanding this axis provides opportunities for therapeutic intervention through:

Restoring metabolic support functions

Modulating inflammatory responses

Enhancing protective mechanisms

Targeting specific disease pathways

The field continues to evolve with new technologies and therapeutic approaches advancing rapidly.

From the [SciDEX Exchange](/exchange) — scored by multi-agent debate

[Phase-Separated Organelle Targeting](/hypothesis/h-ec731b7a) — 0.72 · Target: G3BP1
[Purinergic P2Y12 Inverse Agonist Therapy](/hypothesis/h-f99ce4ca) — 0.71 · Target: P2RY12
[Complement C1q Mimetic Decoy Therapy](/hypothesis/h-1fe4ba9b) — 0.71 · Target: C1QA
[Metabolic Circuit Breaker via Lipid Droplet Modulation](/hypothesis/h-3d993b5d) — 0.66 · Target: PLIN2
[Temporal Decoupling via Circadian Clock Reset](/hypothesis/h-019ad538) — 0.65 · Target: CLOCK
[Fractalkine Axis Amplification via CX3CR1 Positive Allosteric Modulators](/hypothesis/h-ba3a948a) — 0.63 · Target: CX3CR1
[Synthetic Biology Rewiring via Orthogonal Receptors](/hypothesis/h-e3506e5a) — 0.59 · Target: CNO
[Synaptic Phosphatidylserine Masking via Annexin A1 Mimetics](/hypothesis/h-513a633f) — 0.58 · Target: ANXA1

Related Analyses:

[TREM2 agonism vs antagonism in DAM microglia](/analysis/SDA-2026-04-01-gap-001) 🔄
[Microglial subtypes in neurodegeneration — friend vs foe](/analysis/SDA-2026-04-02-gap-microglial-subtypes-20260402004119) 🔄
[TREM2 agonism vs antagonism in DAM microglia](/analysis/SDA-2026-04-02-gap-001) 🔄
[Microglia-astrocyte crosstalk amplification loops in neurodegeneration](/analysis/SDA-2026-04-01-gap-009) 🔄
[Synaptic pruning by microglia in early AD](/analysis/SDA-2026-04-01-gap-v2-691b42f1) 🔄

Pathway Diagram

The following diagram shows the key molecular relationships involving Microglia-Neuron Metabolic Cross-Talk in Neurodegeneration discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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📗 Cite This Artifact

Microglia-Neuron Metabolic Cross-Talk in Neurodegeneration

Microglia-Neuron Metabolic Cross-Talk in Neurodegeneration

Overview

Metabolic Functions of Microglia

Energy Metabolism

Microglia-Neuron Metabolic Cross-Talk in Neurodegeneration

Overview

Metabolic Functions of Microglia

Energy Metabolism

Metabolic Support to Neurons

Neuron-Derived Metabolic Signals

ATP and Adenosine

Fractalkine Signaling

Dysfunction in Neurodegeneration

Alzheimer's Disease

Parkinson's Disease

Amyotrophic Lateral Sclerosis

Therapeutic Implications

Targeting Microglial Metabolism

Emerging Approaches

Clinical Translation

Cross-References

See Also

External Links

Metabolic coupling represents an emerging paradigm in understanding neuron-glia interactions. Recent single-cell transcriptomic studies have revealed microglial metabolic heterogeneity that correlates with brain regional vulnerability in neurodegenerative diseases.

Metabolic Heterogeneity in Disease

Mitochondrial Function in Microglia

Therapeutic Implications

Metabolic Modulation Strategies

Clinical Trials

Future Directions

Historical Context

Conclusion

Neuroimmune Interactions

Pattern Recognition Receptors

Inflammasome Activation

Cytokine Networks

Region-Specific Microglial Function

Vulnerable Regions

Regional Transcriptomic Signatures

Microglia in Normal Brain Function

Surveillance and Scanning

Synapse Elimination

Research Tools and Models

Animal Models

Imaging Techniques

In Vitro Models

Conclusions

Advanced Therapeutic Strategies

TREM2-Targeting Approaches

TREM2 Agonists

TREM2 Biology

CSF1R-Targeting Strategies

Antagonists

Clinical Applications

CX3CR1 Modulation

Agonists

Effects

Microglial Heterogeneity

Single-Cell Perspectives

Brain Regional Variation

Microglia and Neurogenesis

Adult Neurogenesis

In Neurodegeneration

Microglia and Blood-Brain Barrier

BBB Interactions

In Disease

Metabolic Imaging

PET Tracers

MRI Approaches

Computational Models

In Silico Approaches

Conclusion and Future Directions

References

Microglia and Specific Proteinopathies

Tauopathies

Synucleinopathies

TDP-43 Proteinopathies

Prion Diseases