TREM2+ Border-Associated Macrophages

Overview

Border-associated macrophages (BAMs) are a distinct population of tissue-resident macrophages located at the interface between the central nervous system (CNS) and its surrounding membranes. Unlike microglia, which derive from embryonic yolk sac precursors and colonize the brain parenchyma, BAMs originate from both embryonic and adult bone marrow sources and reside in the meninges, choroid plexus, and perivascular spaces. These cells express TREM2 and play critical roles in CNS immune surveillance, CSF filtration, and response to neurodegeneration^{1"A new type of microglia with a distinct tissue distribution"2016 · Nat Neurosci · DOI 10.1038/nn.4200 · PMID 26884220Open reference}.

Key insight: Border-associated macrophages represent a frontline immune defense at brain boundaries. TREM2 expression on BAMs enables detection of lipid-rich debris and патологические aggregates entering the CSF and meningeal spaces.

Types of Border-Associated Macrophages

Meningeal Macrophages

Located in the dura mater, arachnoid mater, and pia mater:

• Dural macrophages: Reside in the dural sinus areas, interact with venous blood

• Arachnoid trabecular macrophages: Found within the arachnoid trabeculae

• Pial macrophages: Lie on the brain surface beneath the pia mater

Perivascular Macrophages

Located along cerebral blood vessels:

• Vascular smooth muscle cell-associated: Along penetrating arterioles

• Capillary-associated: Near the neurovascular unit

• Venular macrophages: Along post-capillary venules

Choroid Plexus Macrophages

Located in the choroid plexus stroma:

• Epithelial-associated macrophages: Near the choroid plexus epithelium

• • Stromal macrophages: Within the connective tissue core

flowchart TD
    subgraph CNS Borders
        A["Brain Parenchyma"] --> B["Pia Mater"]
        B --> C["Subarachnoid Space"]
        C --> D["Arachnoid Mater"]
        D --> E["Dura Mater"]
        E --> F["Skull/Meninges"]
    end

    subgraph BAM Populations
        B --> G["Pial Macrophages"]
        C --> H["Arachnoid Macrophages"]
        D --> I["Duramater Macrophages"]
        F --> J["Meningeal Macrophages"]
    end

    subgraph Perivascular
        A --> K["Perivascular Macrophages"]
        K --> L["Arteriolar"]
        K --> M["Capillary"]
        K --> N["Venular"]
    end

    subgraph Choroid Plexus
        O["Choroid Plexus"] --> P["Choroid Plexus Macrophages"]
    end

    style G fill:#0a1929,stroke:#333
    style H fill:#0a1929,stroke:#333
    style I fill:#0a1929,stroke:#333
    style J fill:#0a1929,stroke:#333
    style K fill:#3a3000,stroke:#333
    style P fill:#0e2e10,stroke:#333

TREM2 Expression in BAMs

Expression Pattern

TREM2 is constitutively expressed on border-associated macrophages:

• Meningeal macrophages: High TREM2 expression

• Perivascular macrophages: Moderate to high expression

• Choroid plexus macrophages: Variable expression

• Comparison to microglia: Similar expression levels

Functional Significance

TREM2 on BAMs enables:

1. CSF sampling: Detection of soluble Aβ, tau, and other pathogens in CSF

2. Blood-brain barrier monitoring: Surveillance of peripheral immune cell entry

3. Meningeal immune response: Rapid response to CNS infection or injury

4. Debris clearance: Phagocytosis of material entering from CNS parenchyma

Role in Neurodegeneration

Alzheimer’s Disease

BAMs contribute to AD through:

• CSF Aβ detection: TREM2+ BAMs may sample and clear Aβ from CSF

• Meningeal inflammation: TREM2 signaling modulates meningeal cytokine production

• Plaque periphery access: BAMs may interact with emerging plaques at early stages

• Vascular clearance: Perivascular macrophages clear Aβ along cerebral vessels

Parkinson’s Disease

In PD, BAMs participate in:

• Alpha-synuclein clearance: TREM2-dependent phagocytosis of extracellular α-syn

• Blood-brain barrier monitoring: Surveillance during BBB disruption

• Dopaminergic region surveillance: Proximity to substantia nigra

Multiple Sclerosis

In demyelinating disease:

• Myelin debris clearance: BAMs phagocytose myelin fragments entering meninges

• Lesion edge activity: Border regions show increased BAM recruitment

• Re-myelination support: TREM2 signaling may support oligodendrocyte function

TREM2-Dependent Functions in BAMs

Phagocytosis

TREM2 on BAMs mediates:

• Lipid-rich debris clearance: Recognition of myelin and membrane fragments

• Apoptotic cell removal: Clearance of dying cells at brain borders

• Protein aggregate handling: Interaction with Aβ and α-syn in CSF

• Foreign particle clearance: Response to pathogens and nanoparticles

Cytokine Production

TREM2 signaling in BAMs modulates:

• Pro-inflammatory cytokines: IL-1β, IL-6, TNF-α (context-dependent)

• Anti-inflammatory cytokines: IL-10, TGF-β during resolution

• Chemokines: CCL2, CCL5 for immune cell recruitment

Tissue Maintenance

BAMs support CNS homeostasis:

• CSF circulation: Support of choroid plexus function

• Vascular integrity: Perivascular macrophage maintenance of BBB

• Meningeal structure: Support of meningeal architecture

Molecular Mechanisms

TREM2 Signaling Cascade

TREM2 (Triggering Receptor Expressed on Myeloid cells 2) activates intracellular signaling through association with TYROBP (DAP12):

flowchart TD
    A["TREM2 Ligand<br/>Lipid/Abeta/alpha-Syn"] --> B["TREM2 Activation"]
    B --> C["TYROBP/DAP12<br/>ITAM Phosphorylation"]
    C --> D["SYK Activation"]
    D --> E["PI3K/Akt Pathway"]
    D --> D1["PLCgamma Pathway"]
    D --> D2["MAPK Pathway"]

    E --> E1["mTOR Activation"]
    E --> E2["Protein Synthesis"]
    E1 --> E3["Cell Growth<br/>Survival"]

    D1 --> F1["Calcium Flux"]
    D1 --> F2["Cytoskeletal Rearragement"]

    D2 --> G1["Inflammatory Gene<br/>Expression"]
    D2 --> G2["Phagocytosis<br/>Genes"]

    G1 --> H["Cytokine Production"]
    G2 --> I["Phagocytic Activity"]

Downstream Pathways

PI3K/Akt Pathway:

• Promotes cell survival and proliferation

• Enhances metabolic activity

• Anti-apoptotic effects through BAD phosphorylation

MAPK/ERK Pathway:

• Controls inflammatory gene transcription

• Regulates cell proliferation

• Integrates stress signals

NF-κB Pathway:

• Coordinates inflammatory responses

• Regulates cytokine and chemokine production

• Controls adhesion molecule expression

Ligand Recognition

TREM2 recognizes diverse ligands relevant to neurodegeneration:

• Lipids: Phosphatidylserine, oxidized phospholipids

• Apolipoproteins: APOE, APOJ/clusterin

• Protein aggregates: Aβ oligomers, α-synuclein fibrils

• Damage-associated molecular patterns (DAMPs): ATP, DNA fragments

Species-Specific Differences

Mouse vs. Human BAMs

Functional Implications

Mouse Models:

• Dural BAMs closely resemble human dural macrophages

• Perivascular macrophages showconserved functions

• Choroid plexus macrophages well-conserved

Human-Specific Features:

• Enhanced TREM2 variant diversity

• Unique age-related changes

• Disease-specific alterations more pronounced

Interaction with Other Cell Types

Microglia

BAMs maintain distinct but complementary relationships with microglia:

flowchart TD
    A["CNS Border"] --> B["BAMs"]
    A --> C["Microglia"]
    B --> D["Parenchymal Surveillance"]
    B --> E["Border Immunity"]
    C --> F["Active Defense"]
    C --> E

    B --> G["Abeta Sampling<br/>from CSF"]
    C --> H["Plaque Phagocytosis"]

    G --> I["Coordinated<br/>Clearance"]
    H --> I

Division of Labor:

• BAMs sample from CSF and meningeal spaces

• Microglia phagocytose parenchymal debris

• Coordinate response to pathology

Astrocytes

BAM-astrocyte interactions include:

• Pro-inflammatory signaling: IL-1β from BAMs activates astrocytes

• Neuroprotective support: TGF-β from BAMs promotes astrocyte support functions

• Barrier maintenance: Coordinated BBB/CFS barrier regulation

Neurons

Direct and indirect neuron-BAM interactions:

• Neurotrophic support: BDNF production by BAMs

• ** synaptic monitoring**: Surveillance of synaptic activity

• Damage response: Clearance of neuronal debris

Disease-Specific Mechanisms

Alzheimer’s Disease

BAMs contribute to AD through multiple mechanisms:

• Early Aβ detection: TREM2+ BAMs may detect Aβ before plaque formation

• Meningeal inflammation: Contributes to meningeal AD pathology

• Vascular clearance: Perivascular Aβ clearance compromised

Therapeutic Implications:

• TREM2 agonist development

• Enhanced meningeal immune modulation

• Perivascular targeting strategies

Parkinson’s Disease

In PD, BAMs show context-dependent roles:

• α-Syn clearance: TREM2-dependent phagocytosis

• BBB monitoring: Enhanced during BBB disruption

• Nigral surveillance: Proximity to vulnerable regions

Amyotrophic Lateral Sclerosis

BAM alterations in ALS:

• Meningeal inflammation: Enhanced in ALS models

• Motor neuron proximity: Border macrophage involvement

• Disease progression: Correlates with progression

Immunological Features

Antigen Presentation

BAMs express MHC class II and can function as antigen-presenting cells:

• MHC II Expression: Constitutive in some subsets

• T cell activation: Can present CNS antigens

• Immune regulation: Modulates border immunity

Chemokine Receptors

BAMs express diverse chemokine receptors:

• CCR2: Monocyte recruitment

• CX3CR1: Fractalkine signaling

• CCR5: Chemokine responsiveness

Comparison to Microglia

Research Methods

Single-Cell Analysis

Key approaches for BAM characterization:

• scRNA-seq: Single-cell transcriptomics

• ATAC-seq: Chromatin accessibility

• CITE-seq: Protein + transcriptomics

Imaging Approaches

• Two-photon microscopy: Live imaging

• Light sheet: Clearing and volumetric imaging

• Electron microscopy: Ultrastructure

Functional Assays

• Ex vivo phagocytosis: Cargo clearance assays

• Organotypic cultures: 3D model systems

• iPSC-derived: Human BAM models

Biomarker Potential

CSF Biomarkers

BAM-derived markers in CSF:

• sTREM2: Soluble TREM2 fragment

• CCL2: MCP-1 levels

• TGF-β: Immunoregulatory status

Imaging Biomarkers

• Meningeal PET: TSPO inflammation

• MRI: Perivascular space alterations

• DTI: White matter changes

Clinical Correlations

BAM-associated biomarkers correlate with:

• Disease stage and progression

• Treatment response

• Genetic risk factors

Genetic Risk Factors

TREM2 Variants

TREM2 genetic variants affect BAM function:

• R47H: Reduced lipid binding, increased AD risk^{6"TREM2 mutations implicated in NAS and FTD impair microglial function"2017 · Mol Brain · DOI 10.1186/s12979-017-0091-0 · PMID 28412928Open reference}

• R62H: Partial loss of function

• T66M: Severe loss of function

Other Risk Genes

• PLD3: Lysosomal function in BAMs

• APOE: Lipid metabolism

• ABI3: Phagocytosis function

Aging Effects on BAMs

Transcriptional Changes

Aging drives profound transcriptional shifts in BAMs^{7"Aging shifts BAM transcriptome"2022 · Aging Cell · DOI 10.1111/acel.13649 · PMID 35796317Open reference}:

• Inflammatory upregulation: Enhanced pro-inflammatory genes

• Metabolic changes: Altered energy metabolism

• phagocytic decline: Reduced clearance capacity

Functional Decline

Age-related BAM changes:

• Phagocytosis: 40-60% reduction in clearance

• Cytokine production: Increased baseline inflammation

• Survival: Reduced resilience to stress

Comparative Anatomy

CNS Border Compartments

Meninges:

• Dura mater: Outer protective layer

• Arachnoid: Web-like structure

• Pia mater: Inner brain covering

Choroid Plexus:

• CSF production site

• Blood-CSF barrier

• Immune-privileged site

Perivascular Spaces:

• Virchow-Robin spaces

• Interstitial fluid drainage

• Immune cell trafficking

Technical Considerations

Isolation Methods

BAMs can be isolated using:

• Enzymatic digestion: Collagenase/trypsin treatment

• Gradient centrifugation: Density separation

• Magnetic selection: Marker-based isolation^{8"Development of a novel method for BAM isolation"2019 · Nat Methods · DOI 10.1038/s41592-019-0501-0 · PMID 31471671Open reference}

Culture Conditions

Primary BAM culture requires:

• Serum-free media: Defined conditions

• GM-CSF: Growth factor support

• M-CSF: Survival factors

Model Systems

• Organotypic brain slices: Ex vivo analysis

• iPSC-derived BAMs: Human models

• Transgenic mice: Genetic studies

Future Directions

Research Priorities

1. Human BAM heterogeneity: Single-nucleus atlas

2. Disease mechanisms: Causal vs correlative

3. Therapeutic targeting: Specific delivery

Unanswered Questions

• BAM origin and maintenance

• CNS vs peripheral contributions

• Temporal dynamics in disease

• Interactions with gut immune axis

Emerging Technologies

• Spatial transcriptomics: Location-specific functions

• Live imaging: Dynamic BAM behavior

• Organ-on-chip: BBB + BAM models

Therapeutic Targets

TREM2-Targeting Approaches

Downstream Modulation

• SYK inhibitors: Block downstream signaling

• CSF1R modulation: Altering BAM populations

• CCR2 antagonists: Reduce recruitment

Cell-Based Therapies

• BAM transplantation: Restoring function

• Targeted delivery: CNS border delivery

• Genetic correction: APOE4 correction

Age-Related Changes

Aging Effects

Aging significantly impacts BAMs:

• Accumulation with age: Increased numbers of BAMs in aged brain

• TREM2 changes: Altered TREM2 expression with age

• Pro-inflammatory shift: Aged BAMs show enhanced inflammatory responses

• Lipid accumulation: Age-related lipid droplet formation

Neurodegeneration Acceleration

Age-related BAM changes may contribute to:

• Reduced clearance efficiency

• Enhanced neuroinflammation

• Impaired tissue repair

• Compromised immune surveillance

Therapeutic Implications

Targeting Strategies

Therapeutic approaches include:

1. TREM2 modulation: Enhance BAM TREM2 signaling

2. Anti-inflammatory approaches: Modulate BAM cytokine responses

3. Age-related interventions: Restore youthful BAM phenotype

4. CSF-directed therapies: Target BAM-accessible CSF compartments

Biomarker Potential

BAMs may serve as biomarkers:

• CSF TREM2: Reflects BAM and microglial TREM2 processing

• Meningeal inflammation: Imaging of meningeal immune activation

• Perivascular changes: MRI indicators of perivascular macrophage activity

See Also

• TREM2 Signaling

• TREM2 Gene

• Perivascular Macrophages

• Microglia

• Disease-Associated Microglia

• Choroid Plexus

• Meningeal Immunity