Table 1.

Preclinical studies of Hericium erinaceus in AD animal models.

Authors	Animal Models	Treatment Method	Behavioral Test	Behavioral Outcome	Mechanism and Physiological Effect
Mori et al., 2011 [48]	5-week-old male ICR mice with Aβ (25–35) and Aβ (35–25)	10 μg of amyloid β (25–35) peptide administered intracerebroventricularly on days 7 and 14 and fed with HE diet (powdered mixture of normal diet and HE), containing 5.5% of (w/w) for 23 days	Y-Maze test NOR	No significant difference observed in alternation behavior between Aβ (25–35) and Aβ (35–25) group HE increased exploration time for novel object than for familiar object in Aβ (25–35) mice, but not Aβ (35–25) mice	Increased hippocampal NGF mRNA expression
Tsai-Teng et al., 2016 [49]	5-month-old female APPswe/PS1dE9 double transgenic mice	Short-term: Oral administration of HE-A and HE-Et (300 mg/kg/day) for 30 days Long-term: Oral administration of HE-My (300 mg/kg/day) for 70–90 days	Nesting	HE-My for 81 days improved nesting behaviors	HE-A or HE-Et for 30 days: Eliminated Aβ plaque burden Prevented recruitment and activation of plaque-associated microglia and astrocytes Promoted proliferation of neuron progenitors Increased neuronal proliferation in the dentate gyrus
Tzeng et al., 2018 [50]	5-month-old female APPswe/PS1dE9 double transgenic mice	Short-term: HE-A or HE-S (30 mg/kg/day) administered through gavage with vehicle for 30 days Long-term: Oral administration of HE-A (10 and 30 mg/kg/day) for 100 days	Burrowing Nesting MWM	HE-A ameliorated learning and spatial memory during the probe trial Deficits in spontaneous burrowing behavior significantly recovered at both 10 and 30 mg/kg of HE-A Impaired nesting behavior significantly recovered at 30 mg/kg of HE-A	HE-A and HE-S decreased Aβ plaque burden and increased cerebral Aβ degradation HE-A decreased Aβ accumulation by inhibiting Aβ production in the cerebrum HE-A and HE-S reduced activation of glial cells in the cerebrum HE-A and HE-S promoted neurogenesis and dendritic complexity in the hippocampus
Zhang et al., 2016 [47]	10-week-old Balb/c female mice with 120 mg/kg of D-gal 20 mg/kg of kg of AlCl3	Subcutaneous injection of 120 mg/kg of D-gal and intragastric administration of 20 mg/kg of AlCl3 once per day for 10 weeks Intragastric administration of polysaccharide-enriched aqueous extract of HE mycelia at dose of 0.3, 1.0, and 3.0 g/kg for 4 weeks	Autonomic activities test MWM Fatigue rotarod test	HE enhanced vertical and horizontal movements in the autonomic activity test HE ameliorated rotarod test endurance time HE reduced MWM escape latency time	Increasing the dose of HE-enhanced AChE and ChAT concentrations in the serum and hypothalamus
Cordaro et al., 2021 [58]	6–8-week-old male Wistar rats with AlCl3	Intraperitoneally administered 70 mg/kg of AlCl3 daily for 6 weeks Control + HE: Oral administration of HE (200 mg/kg) daily by gavage AD + HE: Oral administration of HE (200 mg/kg) daily by gavage	MWM EPM NOR	HE increased animal permanence in target quadrant HE increased time of novel object recognition with high discrimination ratio	HE reduced AlCl3-induced CA1 neuronal degeneration HE increased Nrf2 expression in the hippocampus HE increased antioxidant defense including SOD, CAT, and GSH levels HE reduced NLRP3 inflammasome activation HE decreased phosphorylated Tau, APP overexpression, and Aβ aggregation
Lee et al., 2021 [59]	3-month-old male and female (SAMP8) mice	Low-dose group (108 mg/kg/bw/day), intermediate-dose group (215 mg/kg/bw/day), and high-dose group (431 mg/kg/bw/day) of oral HE-A administration for 13 weeks	Passive Avoidance Task Active Shuttle Avoidance Task	HE-A significantly increased number of avoidance responses Latency time after training increased for passive avoidance test in HE-A groups	HE-A lowered iNOS expression, lowering oxidative stress/inflammation HE-A decreased TBARS levels, decreasing lipid peroxidation HE-A resulted in a downward trend in Aβ plaque (%)

Abbreviations: HE, Hericium erinaceus; APPswe, Amyloid precursor protein; PS1dE9, Presenilin-1; BrdU, Bromodeoxyuridine; HE-A, erinacine A-enriched Hericium erinaceus mycelia; ADL, Activities of daily living; HE-Et, ethanol extract of erinacine A-enriched Hericium erinaceus mycelium; HE-S, ethanol extract of erinacine S-enriched Hericium erinaceus mycelium; MWM, Morris water maze; Aβ, Amyloid-beta; Balb/c, Bagg and albino; AlCl₃, Aluminum; AChE, Acetylcholinesterase; ChAT, Choline acetyltransferase; EPM, Elevated plus maze; NOR, Novel objection recognition; CA1, Carbonic anhydrase 1; Nrf2, Nuclear factor-erythroid 2-related factor 2; SOD, Superoxide dismutase; CAT, Catalase; GSH, Glutathione; NLRP3, NLR family pyrin domain containing 3; NGF, Nerve growth factor; mRNA, Messenger RNA; SAMP8, Senescence accelerated mouse prone 8; iNOS, Induced nitric oxidase synthase; TBARS, Thiobarbituric acid-reactive substances.