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Updated: May 6, 2026
Culturing Microglia from the Neonatal and Adult Central Nervous System
Published on: August 9, 2013
Plasticity of Human Microglia and Brain Perivascular Macrophages in Aging and Alzheimer's Disease
Donghoon Lee1,2,3,4, James M Vicari1,2,3,4, Christian Porras1,2,3,4
1Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Abstract:
The complex roles of myeloid cells, including microglia and perivascular macrophages, are central to the neurobiology of Alzheimer's disease (AD), yet they remain incompletely understood. Here, we profiled 832,505 human myeloid cells from the prefrontal cortex of 1,607 unique donors covering the human lifespan and varying degrees of AD neuropathology. We delineated 13 transcriptionally distinct myeloid subtypes organized into 6 subclasses and identified AD-associated adaptive changes in myeloid cells over aging and disease progression. The GPNMB subtype, linked to phagocytosis, increased significantly with AD burden and correlated with polygenic AD risk scores. By organizing AD-risk genes into a regulatory hierarchy, we identified and validated MITF as an upstream transcriptional activator of GPNMB, critical for maintaining phagocytosis. Through cell-to-cell interaction networks, we prioritized APOE-SORL1 and APOE-TREM2 ligand-receptor pairs, associated with AD progression. In both human and mouse models, TREM2 deficiency disrupted GPNMB expansion and reduced phagocytic function, suggesting that GPNMB's role in neuroprotection was TREM2-dependent. Our findings clarify myeloid subtypes implicated in aging and AD, advancing the mechanistic understanding of their role in AD and aiding therapeutic discovery.
Insights
This study reveals how myeloid cell subtypes change with aging and Alzheimer's disease (AD). A specific subtype, GPNMB, enhances phagocytosis and is linked to AD risk, offering new therapeutic targets.
Area of Science:
- Neurobiology
- Immunology
- Genetics
Background:
- Myeloid cells, including microglia and perivascular macrophages, play crucial roles in Alzheimer's disease (AD) neurobiology.
- Their complex functions and subtypes in AD pathogenesis are not fully understood.
Purpose of the Study:
- To comprehensively profile human myeloid cells across the lifespan and varying AD neuropathology.
- To identify myeloid subtypes and their adaptive changes during aging and AD progression.
- To elucidate the regulatory mechanisms and functional roles of specific myeloid subtypes in AD.
Main Methods:
- Single-cell RNA sequencing of 832,505 myeloid cells from human prefrontal cortex donors.
- Analysis of myeloid cell subtypes, transcriptional regulation, and cell-cell interactions.
- Validation of key genes and pathways in human and mouse models.
Main Results:
- Delineated 13 distinct myeloid subtypes and 6 subclasses, identifying age- and AD-associated changes.
- Found GPNMB subtype, crucial for phagocytosis, increased with AD burden and polygenic AD risk.
- Identified MITF as a transcriptional activator of GPNMB and prioritized APOE-SORL1/TREM2 interactions in AD progression.
- Demonstrated TREM2 dependency for GPNMB function and neuroprotection.
Conclusions:
- Clarified the landscape of myeloid subtypes involved in aging and AD.
- Advanced mechanistic understanding of myeloid cell roles in AD pathogenesis.
- Provided insights for therapeutic strategies targeting myeloid cell functions in AD.
