TABLE 1.
Summary of preclinical studies investigating the efficacy of therapeutics targeting TLR4 for the treatment of AD-like pathology.
| Intervention (References) | Animal model | Treatment regimen | Observations |
| Monophosphoryl lipid A (Michaud et al., 2013) | APP/PS1 transgenic mouse | 50 μg once a week for 12 weeks, IP | • Induced a low inflammatory response while triggering a strong phagocytosis of Aβ in mice • Improved AD-related pathology and enhanced memory function in APP/PS1 mice |
| Thymoquinone (Abulfadl et al., 2018) | Rat model of AD induced by AlCl3 (10 mg/kg/day for 42 days, IP) and D-galactose (60 mg/kg/day for 42 days, IP) | 10, 20, and 40 mg/kg/day for 14 days, IG | • Alleviated cognitive impairment in AD rats • Reduced Aβ deposition • Reduced TNF-α and IL-1β levels • Decreased expression of TLR4, MyD88, TRIF, and downstream effectors including NF-κB and IRF3 |
| Soybean isoflavone (Ding et al., 2011) | Rat model of AD induced by Aβ42 (20 μg/200 μl) | 80 mg/kg/day for 14 days, IG | • Improved learning and memory in rats • Reduced production of pro-inflammatory cytokines IL-1β and TNF-α • Reversed Aβ42-induced upregulation of TLR4 and nuclear translocation of NF-κB p65 |
| Hesperetin (Ikram et al., 2019) | Mouse model of AD induced by Aβ42 (5 μg, ICV) | 50 mg/kg for 6 weeks, ICV | • Reduced lipid peroxidation and reactive oxygen species production and increased Nrf2/HO-1 expression in response to oxidative stress in the brain • Reversed Aβ-induced microglia activation and reduced expression of APP, BACE-1, and Aβ • Attenuated expression of TLR4, p-NF-κB, TNF-α, and IL-1β and proapoptotic proteins such as Bax, Caspase-3, and PARP-1 in neurons • Increased levels of synaptic markers including syntaxin, SNAP-25, PSD-95, Syp, and SNAP-23 Alleviated memory dysfunction |
| Chotosan (Chen et al., 2016) | Mouse model of AD induced by Aβ42 (410 pM) | 750 or 375 mg/kg/day for 3 weeks, IG | • Alleviated memory and cognitive deficits • Attenuated upregulation of TLR4 and NF-κB p65 as well as that of pro-inflammatory cytokines TNF-α and IL-1β • Inhibited neuronal apoptosis, as evidenced by an increase in Bcl-2/Bax ratio and a decrease in the level of proapoptotic protein Caspase-3 |
| Ethyl pyruvate (Chavali et al., 2020) | Rat model of AD induced by AlCl3 (50 mg/kg/day for 28 days, IP) | 50, 100, and 200 mg/kg/day, IG | • Alleviated cognitive impairment • Reduced oxidative stress as assessed by decreased MDA, nitrite, and SOD level and increased catalase and glutathione levels • Decreased expression of TLR4 • Ameliorated deposition of amyloid and neurofibrillary tangles |
| Atorvastatin (Wang et al., 2018) | Rat model of AD induced by Aβ42 (10 μl, ICV) | 5 or 10 mg/kg from 3 weeks before to 6 days after injection of Aβ42, IG | • Alleviated cognitive impairment in rats • Attenuated microglia and astrocyte activation • Suppressed Aβ42-induced apoptosis • Reduced levels of TLR4 and TRAF6 and inhibited NF-κB nuclear translocation |
| Gx-50 (Shi et al., 2016) | APP transgenic mouse | 1 mg/kg for 2 months, IP | • Suppressed microglia activation and expression of IL-1β, iNOS, and COX2 • Blocked Aβ-induced phosphorylation of IκB and NF-κB nuclear translocation • Decreased levels of TLR4, MyD88, and TRAF6 • Inhibited MAPK activation |
| Alpha linoleic acid (Ali et al., 2020) | Mouse model of AD induced by Aβ42 (5 μl, ICV) | 60 mg/kg for 6 weeks, PO | • Attenuated Aβ42-induced activation of TLR4 and reduced GFAP and Iba-1 levels in the frontal cortex and hippocampus • Reduced the expression of p-JNK, p-NF-κB p65 (Ser536), and TNF • Enhanced the expression of APP, BACE-1, and Aβ42 in the brain • Reversed Aβ42-induced cell apoptosis • Increased the expression of synaptic markers (SNAP-23 and PSD-95) • Improved cognitive function |
| TAK-242 (Cui et al., 2020) | APP/PS1 transgenic mouse | 2 mg/kg/day for 28 days, IP | • Promoted M1 microglia switching to an M2 phenotype • Reduced plaque load • Improved cognitive performance • Suppressed inflammatory response by inhibiting MyD88/NF-κB-p65 and NLRP3 |
| Baicalin (Jin et al., 2019) | APP/PS1 transgenic mouse | 103 mg/kg/day for 33 days, IG | • Alleviated deficits in learning and cognition • Blocked neuronal apoptosis • Inhibited microglia activation and production of pro-inflammatory cytokines including IL-1β, IL-18, and iNOS • Suppressed TLR4/NF-κB signaling and activation of the NLRP3 inflammasome |
Aβ, amyloid beta; AD, Alzheimer disease; AlCl3, aluminum chloride; APP, amyloid precursor protein; BACE-1, beta-amyloid–cleaving enzyme 1; Bax, B cell lymphoma 2-activated X protein; Bcl-2, B cell lymphoma 2; COX2, cyclooxygenase 2; GFAP, glial fibrillary acidic protein; HO-1, heme oxygenase 1; Iba-1, ionized calcium-binding adaptor molecule 1; ICV, intracerebroventricular; IG, intragastric; iNOS, inducible nitric oxide synthase; IL, interleukin; IP, intraperitoneal; IRF3, interferon-regulatory factor 3; LPO, lipid peroxidation; MAPK, mitogen-activated protein kinase; MDA, malondialdehyde; MyD88, myeloid differentiation primary response protein 88; NF-κB, nuclear factor kappa B; NLRP3, nucleotide-binding oligomerization domain, leucine- rich repeat, and pyrin domain-containing 3; Nrf2, nuclear factor erythroid 2-related factor 2; PARP, poly(ADP-ribose) polymerase; p-JNK, phosphorylated c-Jun N-terminal kinase; p-NF-κB, phosphorylated nuclear factor kappa B; PO, peroral; PS1, presenilin 1; PSD-95, postsynaptic density 95; SNAP, synaptosomal-associated protein; ROS, reactive oxygen species; SOD, superoxide dismutase, Syp, synaptophysin; TLR4, Toll-like receptor 4; TNF-α, tumor necrosis factor alpha; TRAF6, tumor necrosis factor receptor-associated factor 6; TRIF, TIR domain-containing adaptor protein-inducing interferon-β.