Table 2.

Summaries of studies reporting RAGE inhibition in AD and related pathology.

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	TTP488 treatment ameliorated disease progression dose-dependently. Treatment with TTP488 increased in amyloid burden and reduced inflammatory cytokines	[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	Treatment with sRAGE-MSC decreased apoptotic cells, increased neuron survival and reduced inflammatory cytokines (mRNA of TNF-α, INF-γ and IL-1β) in Aβ1–42 administered rats. Transplanted sRAGE-MSCs showed improved survival rate compared to MSCs as evidenced by elevated mRNA levels of CD44, CD90 and CD117 for sRAGE-MSCs.	[133]
3	Hesperidin (20, 40 and 80 mg/kg)	AD like pathology in APP/PS1 mice	Treatment for 90 days	Treatment with Hesperidin inhibited the increased RAGE expression, the increased phosphorylation of IκBα, terminated nuclear translocation of NF-κB/p65 in the cortex of APP/PS1 mice. Hesperidin reduced oxidative stress (HO-1, SOD, CAT and GSH-Px) and inflammation (TNF-α, CRP, MCP-1 and NF-κB) in cerebral cortex of APP/PS1 mice. Treatment with Hesperidin restored learning and memory dysfunction in APP/PS1 mice as evident by decreased escape latency and increased staying in the target quadrant in MWM trial.	[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	Linguizhugan downregulated the reactive expression levels of RAGE, reduced TNF-α, IL-1β, IL-6, Aβ1–42 as well as inhibit MAPK and NF-κB signaling. Linguizhugan ameliorated Aβ-induced spatial learning and memory deficits in MWM trials and improves brain neuronal damage as evident by increased number of neurons in H&E staining.	[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	FPS-ZM1 bind exclusively to RAGE and inhibited RAGE-driven influx of circulating Aβ40 and Aβ42 into the brain. Treatment with FPS-ZM1 decrease activity of β-secretase activity, Aβ production and inhibited activation of microglia and the neuroinflammatory mediators (TNF-α, IL-1β, IL-6, and CCL2).	[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	-	Inhibition of microglial RAGE prevented synaptic and behavioural deficits and lowered the activation of stress related kinase (p38MAPK and JNK). Blocking of microglial RAGE signaling prevents entorhinal cortex (EC) synaptic impairment at several stages of neurodegeneration in mhAPP mice.	[134]
7	Pentamidine (0.05 μg/mL) (S100β inhibitor)	Aβ-induced (10 μg/mL) AD in C57BL/6J mice	Per day	Pentamidine treatment reduced the expression of GFAP, S100B, and RAGE protein. Treatment with Pentamidine reduces neuroinflammation (NF-ĸB, IL-1β) and exerted neuroprotection in CA1 pyramidal neurons.	[113]
8	Matrine (10 and 50 μM)	APP/PS1 transgenic mice model		Treatment with Matrine inhibited Aβ42-induced cytotoxicity and repress the Aβ/RAGE signaling axis in vitro in SH-SY5Y cells. Matrine treatment downregulated expression of pro-inflammatory mediators (NF-ĸB, IL-1β, and TNF-α), reduced Aβ deposition and ameliorated the memory impairment of AD transgenic mice.	[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);	PF-04494700 treatment was safe and well-tolerated in a subject. PF-04494700 treatment exhibited no consistent or clinical effect on plasma levels of Aβ, inflammatory biomarkers (IL-6, IL-1β and TGF-β-1), or secondary cognitive or functional outcomes in this human trial.	[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	High dose of PF-04494700 (20 mg/d) enhanced the adverse effects and cognitive deficits whereas low dose of PF-04494700 (5 mg/d) exhibited a good safety profile.	[136]

AD, Alzheimer’s disease AD; HMGB1, High mobility group box 1; RAGE, Receptor for advanced glycation end products; 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 1; NINCDS-ADRDA, National institute of neurological and communicative diseases and stroke/Alzheimer’s disease and related disorders association; NF-κB, Nuclear factor κ light chain enhancer of activated B cells; CA, Cornu ammonis; CAT, Catalase; SOD, Superoxide dismutase; TNF-α, Tumor necrosis factor-α, TGF-β1, Transforming growth factor-β1; GFAP, Glial fibrillary acidic protein; MAPK, Mitogen-activated protein kinase; IL, Interleukin; iNOS, Inducible nitric oxide synthase; MWM, Morris water maze.