Table 3.
Effects of chemokine and chemokine receptor manipulations in rodent models of AD
| Chemokine/receptor | Intervention | Model | Outcome | References |
|---|---|---|---|---|
| CX3CL1 | Stereotactical injection of tau into the hippocampus | WT mice | Increased levels of CX3CL1 | Lastres-Becker et al. 2014 |
| CX3CL1 knock-out | APP/PS1 mice |
Increased tau phosphorylation Reduced Aβ accumulation |
Lee et al. 2014 | |
| Deletion of C-terminal membrane-bound fragment of CX3CL1 | APP/PS1 mice |
Increased neuroinflammation Increased tau phosphorylarion |
Lee et al. 2014 | |
| Deletion of C-terminal membrane-bound fragment of CX3CL1 | hTau+/−; Mapt−/− mice |
Reduced CX3CR1 expression Increased neuroinflammation |
Bemiller et al. 2018 | |
| CX3CL1 overexpression | PS19 mice |
Reduced neurodegeneration Cognitive improvement Extended lifespan |
Fan et al. 2020 | |
| Overexpression of C-terminal membrane-bound fragment of CX3CL1 | 5xFAD mice |
Reduced Aβ deposition Decreased APP expression Decreased neuronal loss Increased neurogenesis |
Fan et al. 2019 | |
| Overexpression of soluble CX3CL1 fragment |
rTG4510 mice (3–6 months) |
Reduced tau pathology Reduced microglial activation Reduced neurodegeneration No cognitive improvement |
Nash et al. 2013 | |
| Overexpression of soluble CX3CL1 fragment |
rTG4510 mice (7–8 months) |
Cognitive improvement No effect on tau pathology No effect on neurodegeneration |
Finneran et al. 2019 | |
| Overexpression of soluble CX3CL1 fragment | APP/PS1 mice | No changes in Aβ pathology | Nash et al. 2013 | |
| CX3CR1 | Injection of Aβ into the hippocampus | WT rats | Increased expression of CX3CR1 | Wu et al. 2013 |
| WT rats treated with CX3CR1 siRNA | Reduced microglial activation, neuroinflammation and cognitive impairment | |||
| CX3CR1 knock-out | hAPP-J20 mice |
Exacerbated tau pathology Worsened cognitive decline Increased IL-6 |
Cho et al. 2011 | |
| CX3CR1 knock-out | hTau mice |
Exacerbated tau pathology Worsened cognitive decline Increased microglial activation |
Bhaksar et al. 2010 | |
| CX3CR1 knock-out | CRND8 mice (APPSwe, APPV717F) |
Reduced Aβ levels Increased microglial accumulation around Aβ plaques Increased Aβ phagocytosis by microglia |
Liu et al. 2010b | |
| CX3CR1 knock-out | 3xTg mice |
Decreased neuronal loss No effect on Aβ accumulation and phagocytosis |
Fuhrmann et al. 2010 | |
| CX3CR1 deficiency (CX3CR+/− and CX3CR−/−) |
APP/PS1 mice APPSwe mice |
Reduced Aβ levels Reduced microglial activation Reduced microglial accumulation around Aβ plaques Increased Aβ phagocytosis by microglia |
Lee et al. 2010 | |
| CX3CR1 heterozygosity | APP/PS1 mice |
Reduced Aβ levels Cognitive improvement |
Hickman et al. 2019 | |
| CCL2 | CCL2 knock-out | APP/PS1 mice |
Increased levels of Aβ oligomers Impaired Aβ phagocytosis by microglia Increased cognitive decline Impaired neurogenesis |
Kiyota et al. 2013 |
| CCL2 knock-out | PS1 mice |
Impaired neurogenesis Impaired synaptic plasticity Increased cognitive impairment |
Kiyota et al. 2015 | |
|
CCL2 suppression (AAV-mediated delivery of dominant-negative CCL2 mutant) |
APP/PS1 mice |
Decreased microglia activation Decreased levels of Aβ oligomers and fibrils Cognitive improvement |
Kiyota et al. 2009a | |
| CCL2 knock-out | 5xFAD mice |
Reduced inflammation Reduced accumulation of Aβ plaques Reduced neuronal loss Cognitive improvement |
Gutiérrez et al. 2019a, b | |
| CCL2 overexpression | APP mice |
Increased Aβ deposition Increased accumulation of microglia around plaques Increased phagocytosis of Aβ Increased Aβ oligomerization in microglia Increased cognitive decline |
Kiyota et al. 2009b Yamamoto et al. 2005 |
|
| CCL2 overexpression | rTg4510 mice |
Increased microglia activation Aggravated tau pathology |
Joly-Amado et al. 2020 | |
| CCR2 | CCR2 knock-out | APP/PS1 mice |
Increased oligomeric Aβ accumulation Increased cognitive decline Increased microglia accumulation around plaques Decreased microglia activation and phagocytosis |
Naert and Rivest 2011 |
| CCR2 knock-out | Tg2576 mice |
Decreased Aβ clearance Increased accumulation of Aβ |
Mildner et al. 2011 | |
| CCR2 knock-out | Tg2576 mice |
Increased Aβ accumulation Decreased Aβ clearance by microglia Premature death |
El Khoury et al. 2007 | |
| Transplantation of bone marrow from CCR2 knock-out mice | APP/PS1 mice |
Increased levels of Aβ oligomers Increased cognitive decline |
Naert and Rivest 2012 | |
|
CCL3 CCL4 CCL5 |
Hippocampal injection of Aβ | WT rats | Increased expression of CCL3 in peripheral T lymphocytes | Man et al. 2007 |
| ICV injection of Aβ(1–40) | WT mice | Increased expression of CCL3 | Passos et al. 2009 | |
| ICV injection of Aβ(1–40) | CCL3 knock-out mice |
Protection from astrocytosis, microgliosis and neuroinflammation Reduced cognitive impairment |
Passos et al. 2009 | |
| CCR5 | Hippocampal injection of Aβ | WT rats | Increased CCR5 expression in brain endothelial cells | Li et al. 2009 |
| ICV injection of Aβ(1–40) | CCR5 knock-out mice |
Protection from astrocytosis, microgliosis and neuroinflammation Reduced cognitive impairment |
Passos et al. 2009 | |
|
CXCL1 CXCL2 |
Injection of lentiviral CXCL1 into the hippocampus | Aged WT mice | Increased tau cleavage | Zhang et al. 2015 |
| CXCL8 | Injection of Aβ(1–42) into the hippocampus | WT rats |
Increased expression of CXCL8 Gliosis Accumulation of T cells in brain Neuronal loss |
Liu et al. 2010a Ryu et al. 2015 |
| CXCR2 | Injection of Aβ(1–42) into the hippocampus | WT rats |
Increased expression of CXCR2 Gliosis Accumulation of T cells in brain Neuronal loss |
Liu et al. 2010a Ryu et al. 2015 |
| Treatment with selective CXCR2 antagonist SB225002 | APPSwe mice | Reduced levels of soluble Aβ(1–40) | Bakshi et al. 2008, 2011 | |
| CXCL12 | Injection of Aβ into the brain | WT mice | Increased levels of CXCL12 in injected regions | Wu et al. 2017 |
| ICV injection of CXCL12 | APP/PS1 mice |
Decreased accumulation of Aβ Increased accumulation and activation of microglia around Aβ plaques |
Wang et al. 2012 | |
|
ICV pretreatment with CXCL12 ICV treatment with Aβ |
WT mice |
Decreased neuronal loss Decreased oxidative damage |
Raman et al. 2011 | |
| CXCR4 |
Intranasal treatment with hNGFp Treatment with CXCR4 antagonist AMD3100 |
5xFAD mice | Blockade of CXCR4 resulted in abolishment of hNGFp-induced reduction of cognitive impairment, Aβ plaque load and levels of Aβ oligomers | Capsoni et al. 2017 |
| CXCR3 | CXCR3 knock-out | APP/PS1 mice |
Reduced Aβ levels and pathology Reduced gliosis around Aβ plaques Increased microglial phagocytosis of Aβ Reduced neuroinflammation Increased expression of BDNF Cognitive improvement |
Krauthausen et al. 2015 |
|
CXCR3 knock-out Intracerebral Aβ injection |
WT mice | Increased microglial phagocytosis of Aβ | ||
| CCR3 | CCR3 knock-out | APP/PS1 mice |
Decreased tau phosphorylation Decreased Aβ accumulation Reduced gliosis Cognitive improvement |
Zhu et al. 2017 |
| Treatment with selective CCR3 antagonist YM344031 | APP/PS1 mice |
Decreased tau phosphorylation Decreased Aβ accumulation Reduced gliosis Reduced synaptic loss Cognitive improvement |
Sui et al. 2019 |