Neurodegeneration-Associated Microglia (NAM)

Neurodegeneration-Associated Microglia (NAM)

<table class="infobox infobox-cell">
<tr>
<th class="infobox-header" colspan="2">Neurodegeneration-Associated Microglia (NAM)</th>
</tr>
<tr>
<td class="label">Taxonomy</td>
<td>ID</td>
</tr>
<tr>
<td class="label">Cell Ontology (CL)</td>
<td>[CL:0000095](https://www.ebi.ac.uk/ols4/ontologies/cl/classes/http%253A%252F%252Fpurl.obolibrary.org%252Fobo%252FCL_0000095)</td>
</tr>
<tr>
<td class="label">Database</td>
<td>ID</td>
</tr>
<tr>
<td class="label">Cell Ontology</td>
<td>[CL:0000095](https://www.ebi.ac.uk/ols4/ontologies/cl/classes/http%253A%252F%252Fpurl.obolibrary.org%252Fobo%252FCL_0000095)</td>
</tr>
<tr>
<td class="label">Cell Ontology</td>
<td>[CL:0000129](https://www.ebi.ac.uk/ols4/ontologies/cl/classes/http%253A%252F%252Fpurl.obolibrary.org%252Fobo%252FCL_0000129)</td>
</tr>
<tr>
<td class="label">Gene</td>
<td>Function</td>
</tr>
<tr>
<td class="label">TREM2</td>
<td>Triggering receptor on myeloid cells 2</td>
</tr>
<tr>
<td class="label">TYROBP</td>
<td>TYROBP signaling adaptor</td>
</tr>
<tr>
<td class="label">CD33</td>
<td>Siglec-3 receptor</td>
</tr>
<tr>
<td class="label">APOE</td>
<td>Apolipoprotein E</td>
</tr>
<tr>
<td class="label">SPP1</td>
<td>Osteopontin</td>
</tr>
<tr>
<td class="label">ITGAX</td>
<td>CD11c</td>
</tr>
<tr>
<td class="label">Feature</td>
<td>DAM (Stage 1-2)</td>
</tr>
<tr>
<td class="label">TREM2</td>
<td>Intermedia

Neurodegeneration-Associated Microglia (NAM)

<table class="infobox infobox-cell">
<tr>
<th class="infobox-header" colspan="2">Neurodegeneration-Associated Microglia (NAM)</th>
</tr>
<tr>
<td class="label">Taxonomy</td>
<td>ID</td>
</tr>
<tr>
<td class="label">Cell Ontology (CL)</td>
<td>[CL:0000095](https://www.ebi.ac.uk/ols4/ontologies/cl/classes/http%253A%252F%252Fpurl.obolibrary.org%252Fobo%252FCL_0000095)</td>
</tr>
<tr>
<td class="label">Database</td>
<td>ID</td>
</tr>
<tr>
<td class="label">Cell Ontology</td>
<td>[CL:0000095](https://www.ebi.ac.uk/ols4/ontologies/cl/classes/http%253A%252F%252Fpurl.obolibrary.org%252Fobo%252FCL_0000095)</td>
</tr>
<tr>
<td class="label">Cell Ontology</td>
<td>[CL:0000129](https://www.ebi.ac.uk/ols4/ontologies/cl/classes/http%253A%252F%252Fpurl.obolibrary.org%252Fobo%252FCL_0000129)</td>
</tr>
<tr>
<td class="label">Gene</td>
<td>Function</td>
</tr>
<tr>
<td class="label">TREM2</td>
<td>Triggering receptor on myeloid cells 2</td>
</tr>
<tr>
<td class="label">TYROBP</td>
<td>TYROBP signaling adaptor</td>
</tr>
<tr>
<td class="label">CD33</td>
<td>Siglec-3 receptor</td>
</tr>
<tr>
<td class="label">APOE</td>
<td>Apolipoprotein E</td>
</tr>
<tr>
<td class="label">SPP1</td>
<td>Osteopontin</td>
</tr>
<tr>
<td class="label">ITGAX</td>
<td>CD11c</td>
</tr>
<tr>
<td class="label">Feature</td>
<td>DAM (Stage 1-2)</td>
</tr>
<tr>
<td class="label">TREM2</td>
<td>Intermediate</td>
</tr>
<tr>
<td class="label">APOE</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Type I IFN genes</td>
<td>Present</td>
</tr>
<tr>
<td class="label">Proliferation genes</td>
<td>High</td>
</tr>
<tr>
<td class="label">Disease duration</td>
<td>Early</td>
</tr>
<tr>
<td class="label">Strategy</td>
<td>Compound</td>
</tr>
<tr>
<td class="label">TREM2 agonist</td>
<td>AL002</td>
</tr>
<tr>
<td class="label">TREM2 bispecific</td>
<td>TREM2xCD3</td>
</tr>
<tr>
<td class="label">Anti-APOE antibody</td>
<td>Aprinocarsen</td>
</tr>
</table>

Introduction

Neurodegeneration-Associated Microglia (NAM) are a specialized microglial phenotype identified through single-cell transcriptomics that emerges in response to chronic neurodegeneration. Unlike disease-associated microglia (DAM) or activated microglia, NAM represents a distinct cell state characterized by a specific gene expression signature associated with late-stage neurodegenerative processes[@kerenshaul2017].

Overview

Microglia are the resident immune cells of the central nervous system, derived from yolk sac progenitors early in embryogenesis. In the healthy brain, microglia perform essential homeostatic functions including synaptic pruning, debris clearance, and immune surveillance.

Under neurodegenerative conditions, microglia adopt multiple activation states. The NAM phenotype represents one of these states, characterized by a gene expression profile distinct from both homeostatic microglia and the DAM response seen in early Alzheimer's disease.

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Multi-Taxonomy Classification

Taxonomy Database Cross-References

Morphology & Electrophysiology

• Morphology: neuron associated cell (source: Cell Ontology)
• Morphology can be inferred from Cell Ontology classification

PanglaoDB Marker Cross-References

• Unknown (PanglaoDB):

External Database Links

• [Cell Ontology (CL:0000095)](https://www.ebi.ac.uk/ols4/ontologies/cl/classes/http%253A%252F%252Fpurl.obolibrary.org%252Fobo%252FCL_0000095)
• [OBO Foundry (CL:0000095)](http://purl.obolibrary.org/obo/CL_0000095)
• [Allen Brain Cell Atlas](https://portal.brain-map.org/atlases-and-data/bkp/abc-atlas)
• [CellxGene Census](https://cellxgene.cziscience.com/)
• [Human Cell Atlas](https://www.humancellatlas.org/)
• [PanglaoDB](https://panglaodb.se/)

Taxonomy & Classification

PanglaoDB Marker Cross-References

• Unknown (PanglaoDB):

External Database Links

• [Cell Ontology (CL:0000095)](https://www.ebi.ac.uk/ols4/ontologies/cl/classes/http%253A%252F%252Fpurl.obolibrary.org%252Fobo%252FCL_0000095)
• [OBO Foundry (CL:0000095)](http://purl.obolibrary.org/obo/CL_0000095)
• [Allen Brain Cell Atlas](https://portal.brain-map.org/atlases-and-data/bkp/abc-atlas)
• [CellxGene Census](https://cellxgene.cziscience.com/)
• [PanglaoDB](https://panglaodb.se/)

Molecular Signature

Marker Genes

NAM cells are characterized by elevated expression of:

Distinguishing from DAM

Role in Neurodegeneration

Alzheimer's Disease

NAM microglia are prominently found in:

Pathogenic Functions

• Failed phagocytosis - Impaired clearance of amyloid and debris
• Synaptic loss - May contribute to synapse elimination
• Pro-inflammatory cytokine production - Chronic neuroinflammation
• Iron accumulation - Ferrostatin-sensitive cell death

Protective Functions

• Plaque containment - May limit amyloid spread
• Phagocytic activity - Removal of dead cells
• Trophic support - Limited neurotrophic factor release

TREM2 and NAM Biology

TREM2 Variants

TREM2 genetic variants significantly influence NAM function:

• R47H (AD risk) - Impaired lipid sensing, reduced phagocytosis
• R62H - Intermediate risk
• Q33X (PLOSL) - Loss-of-function, Nasu-Hakola disease

TREM2 Signaling

Aβ/Lipid → TREM2 → TYROBP (DAP12) → SYK → PI3K → Phagocytosis
↓
Inflammation

Therapeutic Targeting

Disease Associations

Alzheimer's Disease

• NAM density correlates with cognitive decline
• TREM2 variant carriers show altered NAM response
• Appears in later disease stages

Parkinson's Disease

• NAM-like cells in substantia nigra
• Associated with α-synuclein pathology
• May contribute to dopaminergic neuron loss

ALS

• Upregulation of NAM markers in motor cortex
• Linked to TDP-43 pathology
• Microglial activation correlates with progression

Frontotemporal Dementia

• NAM cells in affected cortical regions
• Associated with tau and TDP-43 pathology

Therapeutic Implications

Modulating NAM Activity

Biomarker Potential

• TREM2 in CSF - Reflects microglial activation
• sTREM2 - Soluble TREM2 as disease marker
• NAM gene signature - Blood-based RNA signatures

Research Methods

Identification

• Single-nucleus RNA sequencing
• Spatial transcriptomics
• Flow cytometry with surface markers

Animal Models

• 5xFAD mice (amyloid model)
• P301S tau model
• α-synuclein overexpression models
• TREM2 knock-in/knock-out crosses

See Also

• [Microglia](/cell-types/microglia)
• [TREM2](/genes/trem2)
• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)
• [Amyotrophic Lateral Sclerosis](/diseases/amyotrophic-lateral-sclerosis)
• [Dementia with Lewy Bodies](/diseases/lewy-body-dementia)
• [Neuroinflammation](/mechanisms/neuroinflammation-pathway)

Background

The study of Neurodegeneration Associated Microglia (Nam) has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.

Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.

External Links

• [Alzheimer's Disease Neuroimaging Initiative](https://adni.loni.usc.edu/)
• [AMP-AD Consortium](https://www.niagads.org/amp-ad)
• [Allen Brain Atlas - Microglia](https://brain-map.org/)