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Updated: Mar 3, 2026
Correlative Light and Electron Microscopy to Study Microglial Interactions with β-Amyloid Plaques
Published on: June 1, 2016
Immune hyperreactivity of Aβ plaque-associated microglia in Alzheimer's disease
Zhuoran Yin1, Divya Raj2, Nasrin Saiepour3
1Section Medical Physiology, Department of Neuroscience, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; Department of Medical Ultrasound, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Abstract:
Alzheimer's disease (AD) is strongly associated with microglia-induced neuroinflammation. Particularly, Aβ plaque-associated microglia take on an "activated" morphology. However, the function and phenotype of these Aβ plaque-associated microglia are not well understood. We show hyperreactivity of Aβ plaque-associated microglia upon systemic inflammation in transgenic AD mouse models (i.e., 5XFAD and APP23). Gene expression profiling of Aβ plaque-associated microglia (major histocompatibility complex II+ microglia) isolated from 5XFAD mice revealed a proinflammatory phenotype. The upregulated genes involved in the biological processes (gene ontology terms) included: "immune response to external stimulus" such as Axl, Cd63, Egr2, and Lgals3, "cell motility", such as Ccl3, Ccl4, Cxcr4, and Sdc3, "cell differentiation", and "system development", such as St14, Trpm1, and Spp1. In human AD tissue with similar Braak stages, expression of phagocytic markers and AD-associated genes, including HLA-DRA, APOE, AXL, TREM2, and TYROBP, was higher in laser-captured early-onset AD (EOAD) plaques than in late-onset AD plaques. Interestingly, the nonplaque parenchyma of both EOAD and late-onset AD brains, the expression of above-mentioned markers were similarly low. Here, we provide evidence that Aβ plaque-associated microglia are hyperreactive in their immune response and phagocytosis in the transgenic AD mice as well as in EOAD brain tissue. We suggest that Aβ plaque-associated microglia are the primary source of neuroinflammation related to AD pathology.
Insights
Microglia near amyloid-beta plaques in Alzheimer's disease (AD) show heightened immune responses and phagocytosis. These plaque-associated microglia are identified as a primary driver of neuroinflammation in AD.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Alzheimer's disease (AD) pathogenesis involves neuroinflammation, with microglia playing a key role.
- The precise function and phenotype of microglia associated with amyloid-beta (Aβ) plaques remain incompletely understood.
Purpose of the Study:
- To investigate the hyperreactivity and proinflammatory phenotype of Aβ plaque-associated microglia in AD.
- To compare microglia function in transgenic AD models and human AD brain tissue.
Main Methods:
- Gene expression profiling of microglia isolated from 5XFAD transgenic AD mouse models.
- Analysis of microglia markers in laser-captured plaques from early-onset AD (EOAD) and late-onset AD human brain tissue.
Main Results:
- Aβ plaque-associated microglia in transgenic AD mice exhibit a proinflammatory gene expression profile.
- Upregulated genes relate to immune response, cell motility, differentiation, and system development.
- Human EOAD plaques show higher expression of phagocytic and AD-associated genes (e.g., HLA-DRA, APOE, AXL, TREM2, TYROBP) compared to late-onset AD plaques.
Conclusions:
- Aβ plaque-associated microglia are hyperreactive in immune response and phagocytosis in both AD mouse models and human EOAD.
- These microglia are suggested to be the primary source of AD-related neuroinflammation.
