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Walker. Neuroimmunol Neuroinflammation 2020;7:194-214 I http://dx.doi.org/10.20517/2347-8659.2020.09 Page 199

developing AD but the mechanism(s) are still unclear. The possession of APOE e4 allele has also been
associated with increased inflammation in the brain but immunohistochemistry studies have identified
[43]
ApoE protein in neurofibrillary tangles, amyloid plaques and reactive astrocytes [39-42] , not in microglia .
This is surprising as human microglia in culture and isolated brain microglia express high levels of APOE
mRNA and protein. It is possible that the protein is rapidly secreted by microglia after synthesis, but
evidence to date does not support ApoE as a marker for describing microglial activation states in human
brain tissue. Complement C1q protein has also been studied in relation to AD pathogenesis. Antibodies
to C1q have reactivity with amyloid plaques and neurofibrillary tangles in human brains [44,45] . Similar to
[46]
ApoE, cultured brain-isolated microglia express high levels of complement C1q protein , but the reason
microglia do not show immunoreactivity to ApoE or C1q in brain sections is unclear.

Core transcriptional signature of human microglia
A different approach to address the question of an AD-specific microglial gene signature was carried
out by analyzing 9 different datasets obtained from profiling either sorted cells or brain tissue using
[12]
unbiased correction network analysis . Despite the heterogeneity between the datasets, a consensus
list of 249 genes was identified, and when used to compare AD vs. age-matched controls, 52 genes were
identified. Key genes from this list were CD84 (Signaling Lymphocytic activation molecule-5), dedicator
of cytokinesis 2 (DOCK2), hepatitis A virus cellular receptor 2 (HAVCR2), Fc fragment of IgG receptor IIa
(FCGR2A), linker for activation of T cells family member 2 (LAT2), CD86 (B7-2), phosphatidylinositol-
4,5-bisphosphate 3-kinase catalytic subunit gamma (PIK3CG), apoptosis-associated speck-like protein
containing a CARD (PYCARD), tetraspanin-26 (CD37), myosin IF (MYO1F), leukocyte immunoglobulin
like receptor A2 (LILRA2), protein tyrosine phosphatase receptor type C - CD45 (PTPRC), inositol
polyphosphate-5-phosphatase D (INPP5D), CD33, Toll-like receptor-5 (TLR5), SH3 domain and nuclear
localization signals 1 (SAMSN1), integrin alpha M chain - CD11b (ITGAM), dedicator of cytokinesis
8 - Zir3 (DOCK8), ribosomal protein S6 kinase A1 (RPS6KA1), colony stimulator factor-3 receptor
(CSF3R), SLC7A7 (Y+L amino acid transporter 1), Oxidized low-density lipoprotein receptor 1 (OLR1),
chemokine-like factor (CKLF), Parkin co-regulated gene protein (PARCG), lysozyme (LYZ), lymphocyte
antigen 86 (LY86), arachidonate 5-lipoxygenase activating protein (ALOX5AP), Ras and Rab interactor 3
(RIN3), regulator of G-protein signaling 18 (RGS18), colony stimulating factor 2 receptor beta common
subunit (CSF2RB), Rho GTPase activating protein 15 (ARHGAP15), Rho GTPase activating protein 45
(ARHGAP45), regulator of G-protein signaling 10 (RGS10), interleukin 10 receptor subunit A (IL10RA),
macrophage scavenger receptor-1 (MSR1), bridging integrator-2 (BIN2), and cytokine-like 1 (CYTL1).
Most of these have not been studied in AD brain tissues. Another study addressed the issue of microglial
[47]
specific genes by performing meta-analysis of a number of different datasets . This study only examined
rodent gene datasets. Thirteen microglia-enriched genes were identified and 14 genes were differentially
expressed in monocytes/macrophages.

Meta-analyses of multiple microglial-inflammation profiling studies
Complex analyses of a number of different gene expression profiling studies of different disease animal
models, human diseased tissue and sorted murine and human cells identified multiple signatures
(modules) for microglia associated with neurodegeneration. In human material, there appeared to be
elevated expression of genes that were not observed in animal models. The microglia cluster of genes
contain those more highly expressed in microglia compared to other myeloid cells, but these are not
necessarily microglia-specific. The cluster contained Rho GTPase Activating Protein-5 (Arhgap5),
C-C Chemokine receptor-5 (Ccr5), Sialomucin core protein 24 (Cd164), CUB and sushi multiple
domains 3 (Csmd3), Cst3, Cx3cr1, Gcnt1 (Beta-1,3-galactosyl-O-glycosyl-glycoprotein beta-1,6-N-
acetylglucosaminyltransferase), Golgi membrane protein-1 (Golm1), G protein-coupled receptor 155
(Gpr155), G protein-coupled receptor 34 (Gpr34), G protein-coupled receptor 56 (Gpr56), General
Transcription Factor IIH Subunit 2 (Gtf2h2), LPS responsive beige-like anchor protein (LRBA), leucine-