Impact of HMGB1, RAGE, and TLR4 in Alzheimer’s Disease (AD): From Risk Factors to Therapeutic Targeting
Abstract
:1. Introduction
2. The Pivotal Role of Neuroinflammation in AD Onset
3. Evidence of HMGB1 Implication in AD Pathogenesis
4. Implication of RAGE in AD
5. TLR4 Involvement in AD Pathogenesis
6. HMGB1, RAGE, and TLR4 as Potential Clinical Biomarkers of AD
7. HMGB1, RAGE, and TLR4 Inhibition/Blockade as a Potential Therapy against AD
7.1. Effects of HMGB1 Neutralization in AD
7.2. Effects of RAGE Inhibition in AD
7.3. Effects of TLR4 Blockade in AD
8. Discussion and Future Implications
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
References
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S.N. | Interventions | Model | Treatment Schedule | Observations | References |
---|---|---|---|---|---|
1 | HMGB1 short hairpin RNA (shRNA) | Aβ25–35-induced (25 μmol/L) neuroinflammation in hippocampal neuron cultures | Pre-treated for 24 h |
| [18] |
2 | Anti-HMGB1 mAb (1 mg/kg, S.C. injection) (1 injection/week) | 5xFAD transgenic mice overexpressing the mutant human APP | Administered for 1–6 months or 3–6 months |
| [37] |
3 | Glycyrrhizic acid (GA) (50 and 100 mg/kg, I.P.) | LPS (250 μg/kg) -induced neuroinflammation and cognitive impairment in the C57 mice (4–5 weeks old) | Once daily for 1 week |
| [109] |
4 | Glycyrrhizin (GL) (16.8 mg/kg, I.P.) | p35-/-/Tg2576 mice (p35 deletion in Tg2576 mice) | Every alternate day for 1 week |
| [42] |
5 | GL (30 mg/kg, orally) | Surgery induced cognitive decline in C57BL/6 mice | Once daily for 3 days pre-operatively |
| [110] |
6 | GL (30 and 50 mg/kg, orally) | LPS (3 mg/kg, I.P.)-induced neuroinflammation and cognitive impairment in the C57BL/6 mice | Once a day for 3 days prior to LPS injection |
| [108] |
7 | 18α-glycyrrhetinic acid (GA) (20 μg/mL) | AD nematode models (WT Caenorhabditis elegans) | - |
| [132] |
S.N. | Interventions | Model | Treatment Schedule | Observations | References |
---|---|---|---|---|---|
1 | TTP488 (RAGE antagonist) | Transgenic mice overexpressing APP/PS1 | Oral treatment with TTP488 starting at 12 months of age |
| [116] |
2 | sRAGE-mesenchymal stem cells (MSCs) | Aβ1–42 (5 μL; 200 μM) peptides induced AD model in SD rats | sRAGE-MSCs is transplanted for 4 months |
| [133] |
3 | Hesperidin (20, 40 and 80 mg/kg) | AD like pathology in APP/PS1 mice | Treatment for 90 days |
| [118] |
4 | Linguizhugan (2.4, 4.8, or 1.2 g/kg) | Aβ-induced (10 µg) AD model in SD rats | Linguizhugan treatment for 25 days |
| [117] |
5 | RAGE specific inhibitor (FPS-ZM1, 1 mg/kg/d, I.P.) | Male APPsw/0 mice (15 to 17 months old) overexpressing human APP | For 2 months starting at 8 or 15 months of age |
| [115] |
6 | DNMSR (dominant-negative form of RAGE lacking RAGE signaling targeted to microglia) | AD mouse model carrying human mutation of APP (mhAPP) expressing human Aβ | - |
| [134] |
7 | Pentamidine (0.05 μg/mL) (S100β inhibitor) | Aβ-induced (10 μg/mL) AD in C57BL/6J mice | Per day |
| [113] |
8 | Matrine (10 and 50 μM) | APP/PS1 transgenic mice model |
| [114] | |
9 | PF-04494700 (10 or 20 mg) (oral RAGE inhibitor) | Subjects with mild-to-moderate dementia of AD type meeting NINCDS-ADRDA criteria | 10 week randomized, double-blind, placebo-controlled trial with 2 doses of PF-04494700 (10 mg, after a 6-day loading dose of 30 mg/d); and PF-04494700 (20 mg, after a loading dose of 60 mg/d); |
| [135] |
10 | PF-04494700 (RAGE inhibitor) | Double-blind, placebo-controlled trial at 40 several centre, subjects assessed with AD assessment scale-cognitive-subscale | Treatment for 18 months using 2 doses of PF-04494700 60 mg/day for 6 days, then 20 mg daily and 15 mg/day for 6 days, then 5 mg daily |
| [136] |
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 |
| [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) |
| [126] |
3 | Gx-50 (1 mg/kg) | APP transgenic model of AD | Gx-50 administered daily for 2 months at 5 months of age |
| [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 |
| [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. |
| [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 |
| [125] |
7 | Baicalin (BAI) (103 mg/kg administered intragastrically) | APP/PS1 transgenic mice | Treated with BAI once a day for 33 days |
| [122] |
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Paudel, Y.N.; Angelopoulou, E.; Piperi, C.; Othman, I.; Aamir, K.; Shaikh, M.F. Impact of HMGB1, RAGE, and TLR4 in Alzheimer’s Disease (AD): From Risk Factors to Therapeutic Targeting. Cells 2020, 9, 383. https://doi.org/10.3390/cells9020383
Paudel YN, Angelopoulou E, Piperi C, Othman I, Aamir K, Shaikh MF. Impact of HMGB1, RAGE, and TLR4 in Alzheimer’s Disease (AD): From Risk Factors to Therapeutic Targeting. Cells. 2020; 9(2):383. https://doi.org/10.3390/cells9020383
Chicago/Turabian StylePaudel, Yam Nath, Efthalia Angelopoulou, Christina Piperi, Iekhsan Othman, Khurram Aamir, and Mohd. Farooq Shaikh. 2020. "Impact of HMGB1, RAGE, and TLR4 in Alzheimer’s Disease (AD): From Risk Factors to Therapeutic Targeting" Cells 9, no. 2: 383. https://doi.org/10.3390/cells9020383