Toll-Like Receptor 4: A Promising Therapeutic Target for Alzheimer’s Disease

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	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]