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Walker. Neuroimmunol Neuroinflammation 2020;7:194-214 Neuroimmunology
DOI: 10.20517/2347-8659.2020.09 and Neuroinflammation

Review Open Access

Defining activation states of microglia in human
brain tissue: an unresolved issue for Alzheimer’s

disease

Douglas G. Walker 1,2

1 Molecular Neuroscience Research Center, Shiga University of Medical Science, Otsu 520-2172, Japan.
2 Neurodegenerative Disease Research Center, Biodesign Institute, Arizona State University, Tempe, AZ 85497, USA.

Correspondence to: Dr. Douglas G. Walker, Molecular Neuroscience Research Center, Shiga University of Medical Science,
Seta-Tsukinowa-cho, Otsu 520-2172, Japan. E-mail: walkerdg@gmail.com; walker@belle.shiga-med.ac.jp

How to cite this article: Walker DG. Defining activation states of microglia in human brain tissue: an unresolved issue for
Alzheimer’s disease. Neuroimmunol Neuroinflammation 2020;7:194-214.
http://dx.doi.org/10.20517/2347-8659.2020.09

Received: 24 Jan 2020 First Decision: 25 Mar 2020 Revised: 18 May 2020 Accepted: 28 May 2020 Available online: 12 Jul 2020
Science Editor: Jeffrey Bajramovic Copy Editor: Cai-Hong Wang Production Editor: Tian Zhang

Abstract
The development of concepts concerning the role of microglia in different brain diseases has relied on studies of
animal models or human brain tissue, which primarily use antibodies and immunohistochemistry techniques to
make observations. Since initial studies defined increased expression of the major histocompatibility complex II
protein human leukocyte antigen-DR as a means of identifying reactive, and therefore by implication, damage-
causing microglia in Alzheimer’s disease (AD) or Parkinson’s disease (PD), understanding and describing their
activation states has evolved to an unexpected complexity. It is still difficult to ascertain the specific functions of
individual microglia, particularly those associated with pathological structures, using a narrow range of antigenic
markers. As many approaches to developing treatments for AD or PD are focused on anti-inflammatory strategies,
a more refined understanding of microglial function is needed. In recent years, gene expression studies of human
and rodent microglia have attempted to add clarity to the issue by sub-classification of messenger RNA expression
of cell-sorted microglia to identify disease-associated profiles from homeostatic functions. Ultimately all newly
identified markers will need to be studied in situ in human brain tissue. This review will consider the gaps in
knowledge between using traditional immunohistochemistry approaches with small groups of markers that can be
defined with antibodies, and the findings from cell-sorted and single-cell RNA sequencing transcription profiles.
There have been three approaches to studying microglia in tissue samples: using antigenic markers identified
from studies of peripheral macrophages, studying proteins associated with altered genetic risk factors for disease,
and studying microglial proteins identified from mRNA expression analyses from cell-sorting and gene profiling.
The technical aspects of studying microglia in human brain samples, inherent issues of working with antibodies,
and findings of a range of different functional microglial markers will be reviewed. In particular, we will consider

© The Author(s) 2020. Open Access This article is licensed under a Creative Commons Attribution 4.0
International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long
as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license,
and indicate if changes were made.

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