TABLE 2.

Overview of animal studies of herbal medicines in treatment of AD.

Herbal medicine	Object of study	Cohort description	Sample type	Outcome characteristics	References
Curcumin	APPswe/PS1dE9 double transgenic mice	Administration of curcumin for 6 months to the HDC, MDC and LDC with diferent dose-level as 400 mg/kg/day, 200 mg/kg/day, 100 mg/kg/day	Hippocampus tissues	PI3K, p-PI3K, AKT, p-AKT↑; IR, IRS-1↓	Feng et al.
Curcumin	APPswe/PS1dE9 double transgenic mice	treated with different dose-level as 100 mg/kg/day, 200 mg/kg/day, 400 mg/kg/day. In the positive control group, 10 mg/kg/day RSG was used for treatment.	Hippocampus tissues	Cerebral glucose uptake, IGF-1R, IRS-2, PI3K, p-PI3K, Akt, p-Akt↑; IR, IRS-1↓	Wang et al.
Curcumin	Male Wistar rats	orally with curcumin, zinc sulfate, two doses of CurNP and ZnONP, as well as metformin, for 6 weeks.	Hippocampus tissues and blood sample	Aβ, p-tau, redox, inflammation, MAPK/ERK pathway↓	Abdulmalek et al.
Quercetin	The human intestinal epithelial cell line Caco-2	Caco-2 cells were incubated in INDO for 20 min	Mitochondria	Mitochondria dysfunction, oxidative stress↓	Carrasco-Pozo et al.
Resveratrol	Male C57BL/6J mice	HFD mice were treated with/without MET (250 mg/kg/day), RESV (100 mg/kg/day), or COMBO (MET: 250 mg/kg/day, RESV: 100 mg/kg/day) for 5 weeks.	The center and right prefrontal cortex and hippocampus samples	Autophagy↑; BDNF, synaptophysin↓	Yang et al.
Resveratrol	The Zucker diabetic fatty (ZDF) rat model	ZDF rats and their LN were dosed with a SGP Mixture consisting of grape seed extract, concord grape juice and RES by oral gavage for 10 days	Plasma, urine and brain tissues	The bioavailability of resveratrol, the level of resveratrol in the brain↓	Chen et al.
BBR	Male wistar rats and N2a cells	STZ-treated groups include DM, BBr, and Met were fed with high sugar and fat diet until the time for sacrifice.	N2a cell samples and hippocampal tissue	Glucose utilization, PI3k/PGC epsilon pathway↑; Aβ, AD-related neuronal damage↓	Wu et al.
BBR	Chinese hamster ovary (CHO) cells	CHO-APP695 cells were treated with BBR, PIO or a combination of BBR + PIO. Microglial cells were pre-treated with different concentrations of BBR, ranging from 0.3 to 10 μM and incubated for 2 h at 37°C.	Cell samples	basal respiration, pro-inflammatory cytokines in activated microglial cells↓	Wong et al.
BBR	A STZ diabetes rat model feeding with a high-fat diet	Metformin group with intragastrically administrated 0.18 g/kg of metformin hydrochloride and berberine group with intragastrically administrated 150 mg/kg of berberine once a day for 4 weeks.	Serum samples and hippocampus tissues	Cognitive function↑; IR, tau, neuronal apoptosis↓	Zhang et al.
BBR	Male Wistar rats	187.75 mg/kg/d of BBR for BBR group and 184 mg/kg/d of metformin for Met group	Brain tissues	IR, PI3K/Akt/mTOR, MAPK signaling pathways↓	Chen et al.
BBR	Male Sprague–Dawley rats	Alzheimer diabetic rats treated with BBR in a dose of 150 mg/kg and with metformin in dose of 540 mg/kg	Hippocampus tissues and blood samples	Endoplasmic reticulum (ER) stress, memory deficits↓	Xuan et al.
Extracts of P. harmala	Adult male Wistar rats	Normal rats in group III received daily i.p saline for 2 weeks followed by daily doses of P. harmala per se (187.5 mg/kg; p.o) for 4 weeks, lCl3-exposed rats in group IV were treated with the oral doses of P. harmala 30 min after each neurotoxin injection for a period of 4 weeks, starting from the 15th day of AlCl3 injection	Brain tissues	Aβ, p-tau, GSK3β↓	Saleh et al.
Hup A	HFD obese male C57 BL/6 mice and genetic ob/ob mice	Intragastrically administered 0.1 mg or 0.3 mg Hup A per kilogram of body weight per day or vehicle for three mouths.	Brain tissues	insulin, p-Akt↑in high fat-induced mice, but not seen in ob/ob mice	Wang et al.
Geniposide	Adult male C57BL/6J mice	Treatment groups with low (20 mg/kg, 4 mg/mL in saline) and high (100 mg/kg, 25 mg/mL in saline) by oral administration at the beginning of corticosterone treatment. CREB inhibitor 666–15 (20 mg/kg, 4 mg/mL in saline) was treated to 100 mg/kg geniposide treatment group together by I.P. injection.	Blood samples and hippocampus tissues	CREB↑; cognitive dysfunctions↓	Sun et al.
Geniposide	APPswe/PS1dE9 double transgenic AD mice (C57BL/6 background) and primary cortical neurons	Mice: Treated with geniposide (intragastric administration, i.g.) for consecutive 4 weeks at the dose of 5, 10, and 20 mg/kg, respectively. Liraglutide (100lg/kg, i.p.) was used as a positive control.	Blood samples, brain samples, and cell samples	p-Akt↑; P-tau, the phosphorylation of GSK-3β↓	Zhang et al.
		Cultured cells were incubated with 10 lM geniposide in the presence or absence of insulin (10 lM) for indicated times.
Geniposide	APPswe/PS1dE9 double transgenic AD mice (C57BL/6 background) and Primary cortical neurons	Mice: Treated with geniposide (intragastric administration, i.g.) for consecutive 4 weeks at the dose of 5, 10, and 20 mg/kg, respectively. Liraglutide (100lg/kg, i.p.) was used as a positive control.	Brain samples and cell samples	BACE1, IDE↑	Zhang et al.
		Cultured cells were incubated with 10 lM geniposide in the presence or absence of insulin (10 lM) for indicated times.
Sarsasapogenin	Male Sprague Dawley rats and SH-SY5Y cells	Rats: Treated with the low and high doses of Sar (20 and 60 mg/kg), and positive control insulin (5 U/kg). SH-SY5Y cells: low, middle, and high concentrations of Sar group (HG + Sar, 70 mmol/L glucose +0.1, 1, 10 μmol/L Sar, respectively), and positive control insulin group (HG + In sulin, 70 mmol/L glucose +50 mU/l insulin).	Brain and cell samples	BACE1, Akt/GSK-3β cascade↑; Aβ, p-tau↓	Zhang et al.
Asiaticoside	Adult male Sprague-Dawley rats and SH-SY5Y cells	Administered orally with asiaticoside (20 or 40 mg/kg), rosiglitazone (4 mg/kg), or vehicle (10 mL/kg distilled water instead) once daily (9:00 a.m.) for the consecutive 30 days. Pretreatment cells with asiaticoside (0.1, 1 μmol/L) and rosiglitazone (10 μmol/L) for 48 h	Blood samples, brain tissues, and cell samples	Synaptic function↑; cognitive deficits, oxidative stress, PI3K/Akt/NF-κB pathway↓	Yin et al.
Ginsenoside Rb1	C57BL/6N male mice	The ginsenoside Rb1 group (STZ+30 mg/kg ginsenoside Rb1).	Blood samples and brain tissues	Memory and cognitive ability, insulin sensitivity↑; Glucose intolerance↓	Yang et al.
Ginsenoside Rg2	5XFAD mice and HeLa cell lines	Treated with i.p. Injection of 20 mg/kg Rg2 (or DMSO vehicle) once/day, 5 days/week, for 16 weeks. Age-matched wild-type (WT) male mice were used as a negative control. HeLa cells were treated with using 100 ng/mL tetracycline, or 0.1 mM Rg2 with control or ATG7 siRNA for 48 h.	Blood samples, brain tissues, and cell samples	Cognitive behaviors, autophagy↑	Fan et al.
Quercetin	The db/db mice and age-matched wild-type C57BL/6J-db/m mice	db/db + low dosage of quercetin (QL, 35 mg/kg/d, n = 8) and db/db + high dosage of quercetin (QH, 70 mg/kg/d, n = 8).	Brain tissues	Cognition, brain-derived BDNF, Sirtuin type 1↑;insulin, fasting blood glucose↓	Hu et al.
Luteolin	Male C57BL/6J mice	The mice were randomized into four groups: Control diet (CD); control diet + luteolin (CDL, luteolin 10 mg/kg); high-fat diet (HFD); high-fat diet + luteolin (HFDL, luteolin 10 mg/kg)	Blood samples and brain tissues	BDNF, synapsin I, postsynaptic density protein 95↑; cognitive impairment, neuroinflammation, oxidative stress, neuronal insulin resistance↓	Liu et al.
Piperine	STZ induced rats	control (Vehicle only), diabetic control (STZ only), piperine treated (20 mg/kg day, i.p), and sitagliptin (Positive control) treated.	serum samples, pancreatic and brain tissue samples	Cognition↑; the expression of AD-associated genes↓	Kumar et al.
Artemisinin	Wistar rats	Intranasal administration of a single dose of TSP-1-hEDSCs and intraperitoneal administration of artemisinin for 4 weeks.	Blood samples and brain tissues	Aβ, glucose, ROS, TNF-α↓	Poorgholam et al.
Mangifera indica Linn extract (MGF)	The leptin receptor KO mouse db/db	9–12 mice per group (Control = 12, Control-Mangifera indica Linn extract (MGF) = 11, db/db = 10 and db/db-MGF = 9)	Brain tissues and blood samples	Central inflammation, atrophy, body weight, glucose, and insulin levels ↓	Infante-Garcia et al.
Lychee seed extract (LSE)	Male Sprague Dawley rats	Treated with normal saline (NS) 1 mL/kg (negative control), donepezil 0.42 mg/kg (positive control), LSE 0.7, 1.4 and 2.8 g/kg by intragastric (IG) administration once a day (daily) at 8 a.m. for 28 consecutive days.	Blood samples and hippocampus tissues	Cognitive functions↑; neuronal injury, glucose, insulin, Aβ, AGEs, tau↓	Tang et al.
Yuzu extract	Male Sprague-Dawley rats	AD control, AD yuzu, and control (d 7).	Brain tissues and blood samples	Hippocampal insulin signaling↓	Yang et al.
Luteolin, orientin, and isoorientin	RAW 264.7 cells	Treated with 5, 15, and 30 μM of luteolin, orientin, and isoorientin.	Cell samples	Isoorientin: DPPH, NO, and ONOO ↓	Choi et al.
				Luteolin: ROS, AChE, BChE, BACE1, PTP1B↓
Vitexin, isovitexin, and apigenin	RAW 264.7 cells	Treated with various concentrations of vitexin, isovitexin, and apigenin (final concentration; 5, 15, and 30 lM).	Cell samples	Isovitexin: RLAR, HRAR, AGE, AChE, and BChE↓	Choi et al.
				Vitexin: PTP1B↓
				Apigenin: NO production, iNOS and COX-2↓

Symbol explanation: “↑” means upregulating, increasing, improving and so on. “↓” means downregulating, decreasing, impairing and so on.