Table 3.

Summaries of pre-clinical studies investigating TLR4 inhibition in AD-like pathology.

S.N.	Interventions	Model	Treatment Schedule	Observations	References
1	Monophosphoryl lipid A, LPS-derived TLR4 agonist (MPL, 50 μg, I.P.)	AD like pathology in APPswe/PS1 mice	Administered once a week for 12 weeks	TLR4 stimulation with MPL ameliorate AD-like pathology as well as stimulates the phagocytic capacity of innate immune cells. Treatment with MPL reduced Aβ load (number and size of Aβ deposit) in the brain of APPswe/PS1 mice and ameliorated cognitive decline as assessed by T-maze.	[120]
2	MPL (1 μg/5 μL/rat)	Aβ1–42-induced (0.075 μg/hour, I.C.V. for 2 weeks) AD related cognitive decline in male Wistar rats	MPL treatment for 24 days (8 injections alternate 3 days)	Early slight activation of microglia by MPL protect synaptic function and improve learning and memory performance. MPL treatment induced dose-dependent release of TNF-α and CCL-3 from BV-2 cells. Treatment with MPL upregulated hippocampal expression of IL-10 and TGF-1β, and arginase 1.	[126]
3	Gx-50 (1 mg/kg)	APP transgenic model of AD	Gx-50 administered daily for 2 months at 5 months of age	Gx-50 treatment inhibited TLR4-mediated inflammatory (reduced both TLR4 mRNA and TLR4 proteins) signal cascade in microglial cells and in APP-transgenic mice. Gx-50 treatment inhibited the expression of TNF-α, IL-1β, NO, PGE2, iNOS and COX-2 in Aβ treated rat microglia.	[121]
4	Hesperetin (50 mg)	Aβ1–42-induced (5 μL/5min/mouse) AD model in (C57BL/6N, WT) mouse	Hesperetin (50 mg) treatment for 6 weeks	Hesperetin regulates AD-like pathology by regulating APP, BACE-1, and Aβ. Hesperetin treatment conferred neuroprotection via inhibition of oxidative stress (decrease LPO, ROS and increase Nrf2 and HO-1) neuroinflammation (decreased TLR4, p-NF-κB, TNF-α, and IL-1β), apoptotic cell death (decreased Caspase-3 and PARP-1) and cognitive consolidation (MWM and Y-maze).	[123]
5	MG53 (2 mg/kg)	LPS-induced (0.25 mg/kg, I.P. once a day for 1 week) neuroinflammation and neurotoxicity (in vitro and in vivo) in male C57BL/6 mice.	MG53 (once a day for 2 weeks) was intravenously administrated through tail vein one week before LPS injection.	In the hippocampus of LPS treated mice, MG53 treatment inhibited LPS-induced neuroinflammation in vivo (decreases IL-1β, IL-6, TLR4, p-IKBα and p-NF-κB) via inhibiting TLR4/NF-κB signaling. Pre-treatment with MG53 ameliorated LPS induced memory deficits as evident by shorter escape latency, greater portion of time spent in the target quadrant in MWM trail.	[124]
6	Resveratrol	In vitro study (RAW 264.7 cells stimulated with 10 ng/mL LPS, BV-2 cells 100 ng/mL LPS, and Ba/F3 cells with 50 ng/mL LPS) In vivo study in Aβ APP/PS1 transgenic mice	Orally administered for 15 weeks	50 μM resveratrol treatment inhibited cytokine secretion, NF-κB and STAT1/3 signaling LPS-stimulated BV-2 and RAW 264.7 cells. Resveratrol acted upstream in the activation signaling via interfering with TLR4 oligomerization upon TLR4 stimulation. Resveratrol treatment reduced the number of activated microglial cells surrounding amyloid plaques in APP/PS1 mice.	[125]
7	Baicalin (BAI) (103 mg/kg administered intragastrically)	APP/PS1 transgenic mice	Treated with BAI once a day for 33 days	Treatment with BAI ameliorated learning and memory deficits evident by MWM and PAT and prevented neuronal apoptosis (decreased CASP3 protein) in APP/PS1 mice. BAI suppressed microglial activation and pro-inflammatory cytokine levels (mRNA levels of IL-1β, IL-18, and iNOS), inhibited activation of NLRP3 inflammasome and the TLR4/NF-κB signaling axis but did not decrease Aβ deposition in APP/PS1 mice.	[122]

AD, Alzheimer’s disease AD; TLR4, Toll-like receptor 4; Aβ, Amyloid beta; APP, Amyloid precursor protein; PS1, Presenilin 1; MSCs, Mesenchymal stem cells MSCs; IL, Interleukin; IBA1, ionized calcium-binding adapter molecule; NF-κB, Nuclear factor κ light chain enhancer of activated B cells; LPS, Lipopolysaccharide; TNF-α, Tumor necrosis factor-α, LPO, Lipid peroxides; TGF-β1, Transforming growth factor-β1; NLRP3, Nod-like receptor protein 3; ROS, Reactive oxygen species; IL, Interleukin; iNOS, Inducible nitric oxide synthase; MWM, Morris water maze; STAT1/3, Signal transducer and activator of transcription 1/3.