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Updated: Aug 13, 2026
Obtaining Human Microglia from Adult Human Brain Tissue
Published on: August 30, 2020
Plasticity of human microglia and brain perivascular macrophages in aging and Alzheimer's disease
Donghoon Lee1,2,3,4, James M Vicari5,6,7,8, Christian Porras5,6,7,8
1Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York City, NY, USA. donghoon.lee@mssm.edu.
Abstract:
Myeloid cells, including microglia and perivascular macrophages, are central to Alzheimer's disease (AD) neurobiology, yet their role remains incompletely understood. We profiled 832,505 human myeloid cells from the prefrontal cortex of 1,607 donors spanning the lifespan and showing varying degrees of AD neuropathology. We delineated six subclasses comprising 13 transcriptionally distinct subtypes and identified adaptive changes associated with aging and AD progression. Here we show that a disease-associated microglial subtype, characterized by elevated GPNMB expression and enriched for polygenic AD risk, expands with AD pathology and shows increased phagocytic activity. We identify MITF as an upstream regulator required to maintain this microglial state. Cell-cell interaction analyses prioritize APOE-SORL1 and APOE-TREM2 signaling pairs associated with disease progression. Using human and mouse models, we demonstrate that the neuroprotective effects of this microglial subtype depend on TREM2. These findings provide mechanistic insights into myeloid cell function in aging and AD, aiding therapeutic discovery.
Insights
This study reveals how myeloid cells, like microglia, change with aging and Alzheimer's disease (AD). A specific microglial subtype expands in AD, showing increased phagocytic activity and potential therapeutic targets.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Myeloid cells, including microglia and perivascular macrophages, play a key role in Alzheimer's disease (AD) pathogenesis.
- Their precise functions and adaptive changes throughout the lifespan and in AD remain incompletely understood.
Purpose of the Study:
- To comprehensively profile human myeloid cells across the lifespan and in varying degrees of AD neuropathology.
- To identify specific myeloid cell subtypes and their molecular characteristics associated with aging and AD progression.
- To elucidate the mechanisms underlying the function of disease-associated microglia in AD.
Main Methods:
- Single-cell RNA sequencing of 832,505 myeloid cells from the prefrontal cortex of 1,607 human donors.
- Bioinformatic analyses to delineate cell subclasses and subtypes, identify transcriptional changes, and infer cell-cell interactions.
- Functional validation using human and mouse models.
Main Results:
- Six myeloid cell subclasses and 13 transcriptionally distinct subtypes were identified, revealing adaptive changes with aging and AD.
- A specific disease-associated microglial subtype, marked by GPNMB expression and enriched for AD polygenic risk, expands with AD pathology and exhibits heightened phagocytic activity.
- MITF was identified as a key regulator maintaining this microglial state, and APOE-SORL1 and APOE-TREM2 signaling were prioritized in cell-cell interactions.
- The neuroprotective role of this microglial subtype was shown to be dependent on TREM2.
Conclusions:
- This study provides a detailed atlas of human myeloid cell diversity and adaptation in aging and Alzheimer's disease.
- Identified disease-associated microglial subtype and its regulators offer potential therapeutic targets for AD.
- TREM2-dependent neuroprotective functions of specific microglial subtypes highlight their critical role in AD pathogenesis.
