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. 2022 Aug 21;2022:7924199. doi: 10.1155/2022/7924199

Table 1.

Summary of AD therapeutic approaches targeting TLR4.

Intervention Animal model Treatment Mechanism Reference
Hesperetin Aβ1-42-induced AD model in C57BL/6N mice 50 mg/kg treatment for 6 weeks (a) Inhibiting oxidative stress by reducing LPO and ROS and increasing Nrf2 and HO-1
(b) Inhibiting neuroinflammation by reducing TLR4, p-NF-κB, TNF-α, and IL-1β
(c) Inhibiting apoptosis by reducing Bax, caspase-3, and PARP-1
(d) Reducing memory dysfunction by increasing the levels of syntaxin, SNAP-25, PSD-95, Syp, and SNAP-23
[129]

Soybean isoflavone (SIF) Aβ1-42-induced AD model in Wistar rats 80 mg/kg treatment for 14 days (a) Improving learning and memory skills
(b) Inhibiting levels of proinflammatory factors TNF-α and IL-1β
(c) Inhibiting Aβ-induced elevation of TLR4 levels and NF-κB expression in the nucleus
[131]

GX-50 APP transgenic AD model 1 mg/kg/day for 2 months at 5 months of age (a) Inhibiting the expression of TNF-α, IL-1β, NO, PGE2, and iNOS and COX-2 in microglia of Aβ-treated rats
(b) Inhibiting microglia activation and the expression of IL-1β, iNOS, and COX-2 in APP transgenic mice
(c) Inhibiting the activation of NF-κB and MAPK cascades
(d) Reducing TLR4, MyD88, and TRAF6 expressions in vitro and in vivo
[73]

ProBiotic-4 9-month-old senescence-accelerated mouse prone 8 (SAMP8) mice 2 × 109 CFU once daily for 12 weeks (a) Reducing IL-6 and TNF-α levels, plasma, and brain LPS concentrations, TLR4 expression and NF-kB nuclear translocation in the brain, resulting in improved cognitive dysfunction in aged mice [153]

MG136-pMG36e-Glucagon-like peptide-1 (GLP-1) LPS (0.25 mg/kg) for 7 days in male C57BL/6 mice Administered in drinking water for 14 days (a) Attenuating neuroinflammation and improving LPS-induced memory impairment by downregulating the TLR4/NF-κB pathway [159]

TAK-242 Male APP/PS1 transgenic mice 2 mg/kg/day for 28 successive days (a) Inhibiting TLR4 and Bax levels, significantly improves neurological function
(b) Promoting the conversion of microglia from the M1 to the M2 phenotype
(c) Inhibiting MyD88/NF-κB and NLRP3 signaling pathways
[33]

Cattle encephalon glycoside and ignotin (CEGI) Male APP/PS1 transgenic mice; C57BL/6J mice 6.6 ml/kg/day CEGI for 30 days (a) Inhibiting TLR4 expression and NF-κB p65 phosphorylation to exert antineuroinflammatory effects [173]

Fasudil Male APP/PS1 transgenic mice 25 mg/kg/day for 2 months (a) Inhibiting microglia activation and promoting their conversion to an anti-inflammatory phenotype by suppressing TLR4, MyD88, and NF-κB expression, and promoting astrocyte conversion from A1 to A2 phenotype [179]

Atorvastatin Aβ1-42-induced AD model in Sprague-Dawley male rats 5 and 10 mg/kg from 3 weeks before to 6 days after Aβ1–42 injections (a) Reducing TLR4, TRAF6, and NF-κB levels, inhibiting microglia and astrocyte activation, and improving spatial learning ability and memory impairment [37]

Tetrandrine APP/PS1 transgenic 5XFAD mice; Aβ1-42-induced BV2 cells 10, 20, and 40 mg/kg every 2 days from the age of 5 months to 7 months (a) Dose-dependently improving cognitive performance in mice
(b) Promoting reduced amyloid plaque deposition and hippocampal apoptosis in the brain
(c) Inhibiting the expression of inflammation-related genes (TNFα, IL-1β, and IL-6) and TLR4, p65, iNOS, and COX-2
[193]

Pinoresinol diglucoside (PDG) Aβ1-42-induced AD model in BALB/c mice 5 and 10 mg/kg every day for 3 weeks (a) Reversing Aβ1-42-induced memory impairment in mice
(b) Inhibiting the release of proinflammatory cytokines (TNF-α and IL-1β), ROS, and MDA and promotes the activity of antioxidant enzymes (SOD and CAT)
(c) Upregulating the ratio of Bcl-2/Bax and downregulates the expression of Cyt C and cleaved caspase-3, thereby inhibiting neuronal apoptosis
(d) Reducing TLR4 expression and NF-κB p65 activation and promotes Nrf2 and HO-1 expression
[203]

Geniposidic acid (GPA) APP/PS1 transgenic C57BL/6J mice 25, 50, and 75 mg/kg every day for 90 days (a) Improving spatial learning and memory abilities and reducing brain Aβ deposition in mice
(b) Inhibiting the activation of astrocytes and microglia, downregulating the expression of proinflammatory cytokines and iNOS, and upregulating the expression of anti-inflammatory cytokines and Arg-1
(c) Downregulating the expression of TLR2, TLR4, RAGE, MyD88, and NF-κB p65
[204]

Chotosan (CTS) Aβ1-42-induced AD model in ICR male mice 375, 750 mg/kg/day for 3 weeks (a) Improving memory impairment in mice
(b) Decreasing TLR-4 and NF-κB p65 expression and reducing the release of proinflammatory cytokines (including TNF-α and IL-1β) in the hippocampus
(c) Increasing the Bcl-2/Bax ratio and decreasing caspase-3 activity, thereby inhibiting neuronal apoptosis
[213]