Table 1.
Effects of inflammatory mediators on APP, Aβ peptide and TAU in different cellular and animal models.
| APP | APP Processing | Aβ | TAU | Cellular/Animal Models | Refs. | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| CYTOKINES | Pro-Inflammatory | IL-1β | ↑ APP mRNA ↑ or ↓ APP levels |
↑ sAPPα; ↓ sAPPβ ↑ γ-secretase & AICD ↑ α-secretase (ADAM17/TACE) ↓ β-secretase |
↑ or ↓ Aβ1-40 ↓ Aβ1-42 ↓ Aβ deposition ↑ Aβ ↓ Aβ1-40 ↓ Aβ1-42 ↓ Aβ deposition |
↑ TAU mRNA ↑ p-TAU ↓ p-TAU |
Cortical neurons; microglia; neuron-microglial co-cultures Endothelial, neuronal and glial cells IL-1β injected Sprague-Dawley rats IL-1β injected Long-Evans rats Neuroglioma U251 cells Retinal glial cells Neuroblastoma SK-N-SH cells; cortical neurons IL-1β overexpression in APP/PS1 tg mice IL-1β expression in APP/PS1 tg mice APP-based T20 cell line Rat anti-IL-1R blocking mAb injected 3xtg AD mice Cortical neurons; microglia; neuron-microglial co-cultures 3xtg AD/IL-1βXAT mice IL-1β pellet implanted Sprague-Dawley rats |
[64] [67] [68] [69] [70] [71] [72] [73] [74] [88] [65] [132] [135] [136] |
||||
| IL-1α | ↑ or ↓ APP levels | ↑ α-secretase (ADAM10; ADAM17/TACE) ↑ sAPPα |
↓ Aβ1-40
↓ Aβ1-42 |
--- | U373 MG astrocytoma cells | [76] | ||||||
| IL-6 | ↑ or = APP mRNA | --- | ↓ Aβ deposition |
↑ p-TAU | Cortical neurons; glial cells C57BL mice; Staggerer mutant mice Murine IL-6 overexpression in APP tg mice Hippocampal neurons |
[77] [78] [79] [133] |
||||||
| IL-18 | ↑ APP levels ↑ p-APP |
↑ sAPPβ ↑ β-secretase (BACE1) ↑ γ-secretase (PSEN1 & Pen-2) |
↑ Aβ1-40 | ↑ p-TAU | Differentiated SH-SY5Y neuroblastoma cells | [80] [134] |
||||||
| TNF-α | ↑ APP mRNA = APP levels ↓ APP levels |
↑ sAPPβ ↑ β-secretase (BACE1) ↑ γ-secretase & AICD |
↑ Aβ1-40
↑ Aβ1-42 ↑ or ↓ Aβ deposition ↓ Aβ1-40 ↓ Aβ1-42 ↓ or = Aβ deposition |
↑ p-TAU ↓ p-TAU |
APP expressing astrocytes; cortical neurons 3T3-L1 adipocytes Murine TNF-α expression in APP tg mice APP-based T20 cell line 3xtg AD mice/ TNF-α lowering agent (IDT) 3xtg AD mice/TNF-α lowering agent (3,6′-dithiothalidomide) APP/PS1 tg mice/ TNF-α decreasing agent (Infliximab) |
[51] [82] [85] [88] [83] [84] [139] |
||||||
| IFN-γ | = APP levels | ↑ β-secretase (BACE1) ↑ γ-secretase & AICD |
↑ Aβ1-40
↑ Aβ1-42 ↑ or ↓ Aβ deposition |
↓ p-TAU = or ↑ p-TAU |
APP expressing astrocytes; cortical neurons APP tg mice expressing IFN-γ IFN-γ injected B6/SJL mouse / U373 MG astrocytoma cells APP-based T20 cell line INF-γ expression in 3xtg AD mice Neuroglial cultures / JNPL3 mice; rTg4510 mice expressing INF-γ |
[51] [86] [87] [88] [137] [138] |
||||||
| Anti-Inflammatory | IL-4 | = APP levels | = CTFs | ↓ Aβ oligomerization ↑ or ↓ Aβ deposition ↑ Aβ1-40 ↑ Aβ1-42 |
↑ p-TAU | IL-4 expression in APP+PS1 tg mice IL-4 expression in APP/PS1 tg mice Murine IL-4 expression in APP tg mice |
[92] [93] [94] |
|||||
| CYTOKINES | IL-10 | --- | --- | ↑ Aβ deposition ↓ Aβ deposition ↓ Aβ1-40 ↓ Aβ1-42 |
--- | IL-10 expression in APP tg mice APP/PS1/IL10-/- tg mice |
[95] [96] |
|||||
| TGF-β1 | ↑ APP mRNA | --- | ↑ Aβ deposition |
--- | Astrocytes Microglial cell line BV-2 hAPP/TGF-β1 tg mice hAPP/TGF-β1 tg mice |
[98] [99] [100] [101] |
||||||
| Chemotactic |
CCL2 (MCP-1)/ CCR2* |
= APP levels | --- | ↑ Aβ1-40
↑ Aβ1-42 ↑ Aβ deposition ↑ Aβ oligomerization ↑ Aβ1-42 ↑ or = Aβ deposition |
--- | APP/CCL2 tg mice APP/CCL2 tg mice APP/PS1/CCL2-/- tg mice APP/PS1/CCR2-/- tg mice APP/CCR2-/- tg mice |
[105] [106] [107] [108] [109] |
|||||
|
CXCL8 (IL-8)/ CXCR2* |
--- |
↑ γ-secretase substrates (C99; C83) |
↓ Aβ1-40 ↓ Aβ1-42 |
--- |
CHO cell line expressing models; HEKsw cells/CXCR2 siRNA APP/PS1/CXCR2-/- tg mice |
[113] [114] |
||||||
| CXCL10 (IP-10)/ CXCR3* | = APP levels | --- |
↓ Aβ1-40 ↓ Aβ1-42 ↓ Aβ deposition |
--- | APP/PS1/CXCR3-/- tg mice | [117] | ||||||
|
CCL5 (RANTES)/ CCR5* |
--- |
↑ β-secretase (BACE1) ↑ γ-secretase substrates (C99) |
↑ Aβ1-42 ↑ Aβ deposition |
--- | CCR5-/- mice | [119] | ||||||
|
CCL3 (MIP-1α)/ CCR5* |
--- |
↑ β-secretase (BACE1) ↑ γ-secretase substrates (C99) |
↑ Aβ1-42 ↑ Aβ deposition |
--- | CCR5-/- mice | [119] | ||||||
|
CX3CL1 (fractalkine)/ CX3CR1* |
--- | --- |
↓ Aβ1-40 ↓ Aβ1-42 ↓ Aβ deposition |
↑ p-TAU |
APP/PS1/CX3CL1-/- tg mice hTAU-CX3CR1-/- tg mice APP/PS1/CX3CR1-/- tg mice / R1.40/CX3CR1-/- tg mice CRND8/CX3CR1-/- tg mice |
[140] [141] [142] [143] |
||||||
tg: transgenic; CHO: chinese hamster ovary; KO: knockout. References regarding TAU effects are in bold.
Data on cytokines modulators or KO/deficiency, as well as data not directly on chemokine but rather on receptor KO/deficiency (*) is in italics.