Modulating Neuroinflammation as a Prospective Therapeutic Target in Alzheimer’s Disease
Abstract
:1. Alzheimer’s Disease
2. Neuroinflammation
2.1. Microglia
2.2. Astrocytes
3. Receptors Associated with Microglia in Neuroinflammation and AD
3.1. Toll-like Receptors
3.2. Purinergic Receptors
3.3. TREM2
4. Signaling Associated with Microglia in Neuroinflammation and AD
4.1. JAK/STAT Signaling Pathway
4.2. NOD-like Receptor Signaling
4.3. MAPK Signaling
4.4. PI3K/AKT Signaling
4.5. Cyclic Nucleotide Signaling
5. Conclusions
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
References
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Pathway | Model | Target | Refs. |
---|---|---|---|
TLR2/MyD88 | BV-2 cell line | TLR2↓, MyD88↓, NLRP3↓, IL-1β↓, TNF-α↓, IL-6↓, IL-8↓, Iba-1↓ | [96] |
TLR4/NF-κB | APP/PS1 AD mouse model | ROS↓, IL-1β↓, TNF-α↓, IL-6↓, TUNEL-positive cells↓, APOE↑, TREM2↑, APOE↑, TLR4↓, nuclear NF-κB↓, cytoplasmic NF-κB↓, Iba-1↓ | [97] |
TLR4/MyD88 | OVX/D-Gal + scopolamine-induced rat model | Histopathological score↓, intact neuron count↓, Aβ42↓, p-tau↓, NF-κB↓, NLRP3↓, caspase-1↓, IL-1β↓, IL-18↓, TLR4↓, MyD88↓, TRAF-6↓, TAK-1↓, p-JNK↓, CD86-positive microglia↓, CD163-positive microglia↑ | [98] |
TLR3 | APP/PS1 AD mouse model | Aβ↓, Iba-1↓, GFAP↓, CD68↓, NeuN+ cell↑, CD206↓, CD68↓, CD16/32↓, NF-κB↓, IL-1β↓, TNF-α↓, IL-4↑ | [99] |
TLR4/NF-κB | Aβ–ICV-induced mouse AD model, BV-2 cell line | Survival neurons↑, apoptosis index↓, GFAP↓, Iba-1↓, NF-κB↓, TLR4↓, IκBα↓, NeuN+ cell↑, ROS↓, iNOS↓, COX-2↓, TNF-α↓, IL-1β↓, IL-6↓, apoptotic cells↓ | [100] |
TLR and ubiquitin–proteasome | TgF344 AD rat model | Aβ↓, tau PHF↓, amoeboid/ramified microglia↓ | [101] |
P2X7R and PI3K/Akt/GSK3/Nrf2 | Human AD patients, P301S mice, N2a cell line | p-GSK3↑, Nrf2- and FK2-positive intracellular aggregates↓ | [102] |
A1R/A2AR and BDNF | STZ-ICV-induced AD rat model | A1R↑, A2AR↓, TrkB↑, BDNF↑, BUchE↓, cholesterol↓, IL-4↑, IL-10↑ | [103] |
TREM2/NF-κB | SAMP8 mice, BV-2 cell line | iNOS↓, Arg-1↑, IL-10↑, PU.1↑, TREM2↑, p-NF-κB↓, TNF-α↓, IL-6↓, IL-1β↓, p-IKKβ↓ | [104] |
TREM2/TLR4/NF-κB | BV-2 cell line | TREM2↑, TNF-α↓, IL-1β↓, IL-6↓, IL-10↑, CD11b↓, iNOS↓, Arg-1↑ | [105] |
TREM2/PI3K/AKT | Dysfunction mouse model, BV-2 cell line | TREM2↑, p-NR2B↑, BDNF↑, IL-1β↓, IL-6↓, p-PI3K↑, p-AKT↑, Iba-1↓, iNOS↓ | [106] |
JAK/STAT | LPS-induced mouse, BV-2 cell line | IL-1β↓, IL-6↓, TNF-α↓, iNOS↓, JAK↓, STAT↓, Nrf2↑, HO-1↑ | [107] |
NFκB/IL6/STAT3 | APP/PS1 AD mouse model, HT-22, BV2 cell line | NeuN↑, Aβ↓, p-STAT3↑↓, iNOS↓, p65↓, IL-6↓, IL-1β↓, IL-6↓, TNF-α↓ | [108] |
JAK2/STAT3 | Scopolamine-induced BALB/c mouse, LPS- and Aβ-treated BV-2 cell line | AchE↓, ChAT↓, p-JAK2↓, p-STAT3, iNOS↓, Arg-1↑, IL-1β↓, IL-6↓, TNF-α↓, IL-12↓, IL-4↑, IL-10↑ | [109] |
JAK/STAT | LPS-treated BV-2 cell line, primary microglial | NO↓, IL-6↓, TNF-α↓, COX-2↓, iNOS↓, p-ERK↑, p-JNK↓, p-p38↓, IL-11↓, JAK2↓, Tyk2↓, STAT1↓, STAT3↓, neurite length↑ | [110] |
JAK1–STAT6 | APP/PS1 AD mouse model, BV-2 cell line | p-JAK1↑, p-STAT6↑, SOCS3↑, CD206↑, Iba-1↑ | [111] |
Autophagy–NLRP3 inflammasome, PINK1/Parkin | APP/PS1 AD mouse model | AchE↓, MDA↓, IL-1β↓, MCP-1↓, IL-6↓, IL-18↓, TNF-α↓, SOD↑, Aβ plaques↓, tau↓, LC3B↑, p62↓, PINK1↑, parkin↑, beclin1↑, LC3II/LC3I↑, NLRP3↓, ASC↓, cleaved caspase-1↓ | [112] |
SIRT6/NLRP3 | Aβ–ICV-induced AD rat model | SIRT6↑, H3K9Ac↓, p-NF-κB↓, IκBα↓, NLRP3↓, ASC↓, caspase-1↓, cleaved caspase-1↓, GSDMD↓, IL-18↓, Iba-1↓, GFAP↓, COX-2↓, TNF-α↓, ROS↓, NO↓, IFN-γ↓, IL-1β↓, IL-6↓, ROS↓, MDA↓, IL-4↑, IL-10↑, TGF-β↑, SOD↑, GSH↑ | [113] |
NLRP3 | HMC-3 human microglia cell line, scopolamine-induced mouse model | JC-1↓, NLRP3↓, NF-κB↓, vimentin↓, ROS↓, AchE↓, BChE↓, MDA↓, SOD↑, catalase↑ | [114] |
NLRP3/GSDMD | STZ-ICV-induced mouse model (C57BL/6J) | NLRP3↓, caspase-1↓, IL-1β↓, GSDMD↓, caspase-3↓ | [115] |
NLRP3/caspase-1 | Aβ-treated BV-2 cell line, APP/PS1 AD mouse model | NLRP3↓, ASC↓, caspase-1↓, IL-1β↓, IL-18↓, ROS↓ | [116] |
NLRP3 | 3xTg AD mouse model | p-tau↓, Aβ↓, p-GSK3β↑, NeuN↑, Bcl-2↑, Bax↓, Iba-1↓, GFAP↓, IL-1β↓, TNF-α↓, IL-6↓, IL-18↓, p-NF-κB, IKKβ↓, NLRP3↓, ASC↓, caspase-1↓, GSDMD-N↓ | [117] |
NLRP3 | LPS- + IFN-γ-treated BV-2 cell line | TNF-α↓, IL-6↓, IL-1β↓, NLRP3↓, ASC↓, caspase-1↓, CD11b↓, ROS↓ | [118] |
TLR4/MAPK | APP/PS1 AD mouse model | Aβ↓, MDA↓, SYP↑, PSD95↑, IL-1β↓, IL-6↓, TNF-α↓, COX-2↓, CD14↓, Fos↓, Igf2↓, MAPK13↓, CCL3↓, CCL4↓, TREM2↑, TLR4↓, MyD88↓, JNK↓, p38↓, Iba-1↓, CD86↓, iNOS↓, ARG1↑, CD206↑, IL-1β, IL-6, TNF-α↓CD86, iNOS↓, ARG1, TREM2↑, TLR4, MyD88, JNK, p38↓ | [119] |
MAPK | LPS-treated BV-2 cell line | NO↓, iNOS↓, COX-2↓, p-p38↓, p-JNK↓, p-ERK↓, NLRP3↓, ASC↓, cleaved-caspase-1↓, IL-1β↓, pro-IL-1β↑, PGE2↓, TNF-α↓, IL-6↓ | [120] |
MAPK/NF-κB | LPS-treated BV-2 cell line | NO↓, PGE2↓, IL-6↓, TNF-α↓, MCP-1↓, COX-2↓, p-ERK↓, p-JNK↓, p-p38↓, p-IκB↓, p-p65↓ | [121] |
MAPK/ERK | APP/PS1 AD mouse model, LPS-treated BV-2 cell line | Aβ plaques↓, Iba-1↓, GFAP↓, p-ERK1/2↓, c-FOS↓, FOSB↓, FOSL1↓, ROS↓, iNOS↓, NO↓, IL-1β↓, IL-6↓, TNF-α↓, COX-2↓ | [122] |
MAPK/ERK | 3xTg AD mouse model | Aβ25-35↓, TNF-α, ↓ IL-1β↓, IL-6↓NeuN↑, CD31↑, GFAP↓, VCAM-1↓, ICAM-1↓, p-ERK↓, p-MAPK↓, Aβ1–42↓, p-tau↓ | [123] |
p38/NLRP3 inflammasome | 3xTg AD mouse model, BV-2 cell line | Aβ plaque↓, PSD95↑, synaptophysin↑, TNF-α↓, IL-1β↓, IL-6↓, IL-4↑, IL-10↑, Iba-1↓, CD16↓, Arg1↑, NLRP3↓, ASC↓, caspase-1↓, IL-18↓, FIS1↓, DRP1↓, OPA1↑, MFN2↑, TFAM↑, NRF1↑, p-p38↓, JC-1↓ | [124] |
MAPK/p38 | LPS-treated BV-2 cell line, 5XFAD AD mouse model | IL-6↓, IL-1β↓, IL-12↓, TNF-α↓, p-p38↓, Aβ↓, Iba-1↓, GFAP↓, p-tau↓ | [125] |
PI3K/AKT | APP/PS1 AD mouse model | iNOS↓, CD11b↓, TREM2↑, TMEM119↑, Iba-1↓, Aβ↓, p-AKT↑, p-PI3K↓, p-tau↓, IL-1β↓, NF-κB↓, iNOS↓ | [126] |
PI3K/AKT/mTOR | AlCl3-triggered AD rat model | Aβ↓, PI3K↑, AKT↑, mTOR↑, GSK3β↑, BACE-1 ↓, p-tau↓, iNOS↓, NF-κB↓ | [127] |
PI3K/AKT | LPS-ICV-induced mouse | iNOS ↓, pro-IL-1β↓, NO↓, GSK3β↑, SOD↑, GPX1↑, CREB↑ | [128] |
PI3K/AKT | 5xFAD AD mouse model | Thioflavin↓, Iba-1↓, GFAP↓, NF-κB↓, p-IκBα↓, p-AKT↓ | [129] |
PI3K/AKT/GSK3β | APP/PS1 AD mouse model | Iiba-1↓, Aβ↓, p-AKT↑, p-PI3K↑, p-tau↓, GSK3β↑ | [130] |
PDE4 | Rotenone, oral injection, rat model | DA level↑, PDE4 activity↓, pCREB↑, PKA↑, PP-1↓, BDNF↑, NGF↑, NF-κB↓, GSH↑, IL-6↓, TNF-α↓ | [131] |
PDE3 | C57BL/6 (23 months) | NOR↓, GFAP↓, Iba-1↓ | [132] |
PDE2 | MCAO C57BL/6 | PDE2↓, cerebral edema↓, TNF-α↓, IL-6↓, IL-1β↓, MCP-1↓, NF-κB↓, PKA↑, Iba-1↓ | [133] |
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Lee, E.; Chang, Y. Modulating Neuroinflammation as a Prospective Therapeutic Target in Alzheimer’s Disease. Cells 2025, 14, 168. https://doi.org/10.3390/cells14030168
Lee E, Chang Y. Modulating Neuroinflammation as a Prospective Therapeutic Target in Alzheimer’s Disease. Cells. 2025; 14(3):168. https://doi.org/10.3390/cells14030168
Chicago/Turabian StyleLee, Eunshil, and Yongmin Chang. 2025. "Modulating Neuroinflammation as a Prospective Therapeutic Target in Alzheimer’s Disease" Cells 14, no. 3: 168. https://doi.org/10.3390/cells14030168
APA StyleLee, E., & Chang, Y. (2025). Modulating Neuroinflammation as a Prospective Therapeutic Target in Alzheimer’s Disease. Cells, 14(3), 168. https://doi.org/10.3390/cells14030168