Related Experiment Video
Updated: May 8, 2026
Correlative Light and Electron Microscopy to Study Microglial Interactions with β-Amyloid Plaques
Published on: June 1, 2016
Human microglia differentially respond to β-amyloid, tau, and combined Alzheimer's disease pathologies in vivo
Morgan A Coburn1,2,3,4, Ghazaleh Eskandari-Sedighi2,3, Jonathan Hasselmann1,2,3
1Department of Neurobiology and Behavior, University of California, Irvine, California, USA.
Introduction:
Recent studies have identified important species-dependent differences in the response of microglia to β-amyloid (Aβ) pathology. Yet, whether human microglia also interact differently with the pathognomonic combination of amyloid and tau pathologies that occur in Alzheimer's disease (AD) remains unclear.
Methods:
We generated a xenotolerant mouse model of AD that develops both plaque and tangle pathologies, transplanted stem cell-derived microglial progenitors and examined the interactions between human microglia and AD pathologies with scRNA sequencing, immunohistochemistry, and in vitro modeling.
Results:
The combined amyloid and tau pathologies induced robust type-I interferon and proinflammatory cytokine responses, as well as an increased adoption of a distinct "rod" morphology in human microglia. The rod morphology could be induced with type-I interferon treatment in vitro.
Discussion:
We provide new insights into human microglial responses to combined AD pathologies and a novel platform to investigate and manipulate human microglia in vivo.
Highlights:
Amyloid pathology promotes the rapid development of neurofibrillary tangles and neuronal loss in a novel chimeric model of AD. Combined Alzheimer's disease pathologies lead to an expansion of disease-associated microglia (DAM) and exacerbate Interferon-responsive and cytokine/chemokine-enriched states in xenotransplanted human microglia. The combination of amyloid and tau promotes the development of a distinctive rod microglial phenotype that closely correlates with tau pathology and neurodegeneration. Rod morphology and transcriptional changes can be modeled in vitro by treatment of induced pluripotent stem cells (iPSC) -microglia with type-I interferons.
Insights
Human microglia exhibit unique responses to combined Alzheimer's disease (AD) pathologies, developing a distinct "rod" shape and interferon-driven inflammatory states. This study offers a new model for investigating human microglia in AD research.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Species-specific microglial responses to beta-amyloid (Aβ) pathology are known.
- The interaction of human microglia with combined amyloid and tau pathologies in Alzheimer's disease (AD) is not well understood.
Purpose of the Study:
- To investigate how human microglia respond to the combined pathologies of amyloid and tau in Alzheimer's disease.
- To develop a novel in vivo model for studying human microglia in the context of AD.
Main Methods:
- Generation of a xenotolerant mouse model of AD with both plaque and tangle pathologies.
- Transplantation of human stem cell-derived microglial progenitors into the mouse model.
- Analysis using scRNA sequencing, immunohistochemistry, and in vitro modeling.
Main Results:
- Combined amyloid and tau pathologies induced robust type-I interferon and proinflammatory cytokine responses in human microglia.
- Human microglia adopted a distinct
- rod
- morphology, which could be replicated in vitro with type-I interferon treatment.
- Amyloid pathology accelerated neurofibrillary tangle development and neuronal loss in the AD model.
Conclusions:
- Human microglia display unique responses to combined AD pathologies, including a distinctive rod morphology and interferon-driven inflammatory states.
- The study provides a novel platform for investigating and manipulating human microglia in vivo for AD research.
- The findings highlight the role of type-I interferons in microglial responses and morphology in AD.
