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Walker. Neuroimmunol Neuroinflammation 2020;7:194-214 I http://dx.doi.org/10.20517/2347-8659.2020.09 Page 201

Table 2. Prominent microglia genes that are altered with age [50]
Upregulated Downregulated
CTSD CD83
GRN FLT1
LTBR ILIB
TSPO PTGS2
CYBA CCL4
CD14 CCL2
C1QA CCL3
C1QC TLR4
IRF7 PTGER1
TGFBR2
MRC1

Table 3. Human microglia associated genes that change with aging [51]
Cell adhesion/axonal guidance Cell surface receptors
Upregulated Downre gulated Upregulated Downregulated
CAECAM1 ADGRE5 CD163 IFNGR1
CDH3 CDH12 CLEC2B IL6R
DOCK1/5 CDH19 CLEC5A LPAR1
NLGN2 CHL1 CXCR4 LPAR5
NRP1/2 ICAM3 IGF2R MRC2
PLXNC1 ROBO2 P2RX1 MST1R
PCDHGA2/4-8 SEMA3C TNFRSF14 NTRK2
PDHGB2-4 SEMA7A IL15 P2YR12
PTK7 CLEC17A
ROBO4 TLR10
SE MA4A TREML4

[51]
of human and rodent microglia . The paper contained large datasets of differentially expressed microglia
genes with aging but the key finding was the altered expression of genes associated with cell adhesion, cell
motility and different cell surface receptors [Table 3].

The microglia genes related to cell adhesion and axonal guidance were altered in aged microglia.
Upregulated genes were: carcinoembryonic antigen-related cell adhesion molecule 1-CD66a (CAECAM1),
cadherin-3 (CDH3), dedicator of cytokinesis-1/-5 (DOCK1/5), neuroligin-2 (NLGN2), neuropilin-1/-2
(NRP1/2), Plexin C1 (PLXNC1), protocaderin gamma -2,-4, 8 (PCDHGA2/4/8), protocadherin beta-
2, -4 (PCDHGB-2, -4), protein tyrosine kinase-7 (PTK7), roundabout guidance receptor 4 (ROBO4),
and Semaphorin 4A (SEMA4A). Downregulated genes were: ADGRE5 (Adhesion G-protein-coupled
receptor CD97), Cadherin-12 (CDH12), CHL1, intercellular adhesion molecule-3 (ICAM3), roundabout
guidance receptor 2 (ROBO2), Semaphorin 3A (SEMA3C), and Semaphorin 7A (SEMA7A). Immune
receptor-related genes were also altered in aged microglia. Upregulated genes were: CD163 (Hemoglobin
scavenger receptor), C-type lectin domain family 2B (CLEC2B), C-type lectin domain family 5A
(CLEC5A), Chemokine receptor type 4 (CXCR4), insulin growth factor 2 receptor (IGF2R), purinergic
receptor X1 (P2RX1), tumor necrosis factor receptor superfamily14 (TNFRSF14), and interleukin-15
(IL15). Downregulated genes were: interferon gamma receptor 1 (IFNGR1), interleukin 6 receptor (IL6R),
lysophosphatidic acid receptor 1 (LPAR1), lysophosphatidic acid receptor 5 (LPAR5), mannose receptor
C type 2 (MRC2), macrophage stimulating 1 receptor (MST1R), neurotrophic receptor tyrosine kinase
2 (NTRK2), purinergic receptor Y12 (P2RY12), C-type lectin domain family 17A (CLEC17A), toll-like
receptor 10 (TLR10) and triggering receptor expressed on myeloid cells like-4 (TREML4).

ROLE OF CLASSICAL PRO-INFLAMMATORY CYTOKINES IN AD NEUROINFLAMMATION
The early theories of the role of neuroinflammation in AD suggested the involvement of classical