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
(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
(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
(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
(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
(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
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
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
(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
(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
(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