Immune hyperreactivity of Aβ plaque-associated microglia in Alzheimer's disease

Zhuoran Yin, Divya Raj, Nasrin Saiepour, Debby Van Dam, Nieske Brouwer, Inge R. Holtman, Bart J.L. Eggen, Thomas Möller, Joseph A. Tamm, Aicha Abdourahman, Elly M. Hol, Willem Kamphuis, Thomas A. Bayer, Peter P. De Deyn, Erik Boddeke*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

146 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)115-122
Number of pages8
JournalNeurobiology of Aging
StatePublished - Jul 2017
Externally publishedYes


  • Beta-amyloid
  • Early-onset Alzheimer's disease
  • Late-onset Alzheimer's disease
  • Microglia
  • Neurodegeneration
  • Neuroinflammation

ASJC Scopus subject areas

  • Neuroscience(all)
  • Aging
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology


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