The P301S transgenic mice [B6C3-Tg (Prnp-MAPT*P301S) PS19 Vle/J], originally obtained from the Jackson laboratory (Bar Harbor, ME, USA), were used as a model of tauopathy. The female mice at the age of 5 months were randomly allocated to three treatment groups (7 mice/group) corresponding to vehicle control, 3 mg/kg LA (T5625, Sigma, St. Louis, MO; the dosage was calculated everyday based on weight), and 10 mg/kg LA. LA was administered by intraperitoneal injection once per day (no injection was administered one day every three days), and vehicle control mice received physiological saline.

The P301S transgenic mice [B6C3-Tg (Prnp-MAPT*P301S) PS19 Vle/J], originally obtained from the Jackson laboratory (Bar Harbor, ME, USA), were used as a model of tauopathy. The female mice at the age of 5 months were randomly allocated to three treatment groups (7 mice/group) corresponding to vehicle control, 3 mg/kg LA (T5625, Sigma, St. Louis, MO; the dosage was calculated everyday based on weight), and 10 mg/kg LA. LA was administered by intraperitoneal injection once per day (no injection was administered one day every three days), and vehicle control mice received physiological saline.

All animal experiments were approved by the Animal Ethics Committee of Jilin University (permit No. SY201905013) and were conducted in compliance with the ARRIVE guidelines. Eight-month-old B6C3-Tg (APPswePSEN1dE9)/Nju double transgenic male mice (APP/PS1) (genotype: (Appswe) T, (Psen1) T) and age-matched wild-type (WT) (genotype: (Appswe) W, (Psen1) W) male mice were purchased from Nanjing Biomedical Research Institute of Nanjing University. All mice were individually housed at 24 with food and drinking water availablead libitum. After 1 week of adaption in the new environment, WT mice received oral administration of normal saline (10 mL/kg) and were designated as the control group (n = 12). APP/PS1 mice were randomly divided into two groups: the model group (n = 12) received oral administration of normal saline (10 mL/kg) and the agent-treated group (n = 12) received oral treatment with 30 mg/kg FA (L-012-171216, 98.83% purity, Chengdu Herbpurify Co., Ltd., Chengdu, China) beginning on day 8. After 30-day treatment, behavioral experiments were serially performed. The entire treatment protocol lasted for 42 days. Blood samples were collected from the caudal vein. After euthanasia via CO2 inhalation, organs including the brain, liver, spleen, and kidney were collected for further analysis.

Male 6-month-old senescence-resistant R1 (SAMR1) and SAMP8 mice (weight, 28-35 g) were purchased from Beijing SPF Biotechnology. First, mice were placed in the center of an empty testing arena (40 x 40 x 40 cm) and allowed to move freely for adaptation. Next, in the training stage, two similar objects were presented in the testing arena and mice were allowed to explore for 10 min, for 3 consecutive days. On day 4, one of the two familiar objects was replaced by a new object. The time of exploring a novel object or familiar object in 10 min was recorded.

SAMP8 mice were employed as an AD model and were treated with salidroside for 12 weeks. Behavioral tests, immunohistochemistry, HE and Nissl staining, immunofluorescence, transmission electron microscopy, quantitative proteomics, bioinformatic analysis, flow cytometry, iron staining,western blotting, andmolecular dockingwere performed.

APPswe/PSEN1dE9 (APP/PS1) double transgene mice, which were generated by the introduction of human APPswe and PS1-dE9 mutations onto the C57BL/6 background and also wild type (WT) littermates, aged 5 months, were purchased from Beijing HFK Bioscience Co., Ltd. (Beijing, China). The mice received food and water ad libitum under standard husbandry conditions (22-25, 55-65% relative humidity, and 12h/12h lightdark cycle) and acclimated 1 week for the experiments. Mice were randomly divided into 5 groups, including WT control group, APP/PS1 model group, and APP/PS1 + TSG (60, 120 and 180 mg/kg) different dosage groups. Mice were orally treated with TSG every other day for 2 months. WT and model groups were treated with equivalent vehicle.

All animal experiments were approved by the Animal Ethics Committee of Jilin University (permit No. SY201905013) and were conducted in compliance with the ARRIVE guidelines. Eight-month-old B6C3-Tg (APPswePSEN1dE9)/Nju double transgenic male mice (APP/PS1) (genotype: (Appswe) T, (Psen1) T) and age-matched wild-type (WT) (genotype: (Appswe) W, (Psen1) W) male mice were purchased from Nanjing Biomedical Research Institute of Nanjing University. All mice were individually housed at 24 with food and drinking water availablead libitum. After 1 week of adaption in the new environment, WT mice received oral administration of normal saline (10 mL/kg) and were designated as the control group (n = 12). APP/PS1 mice were randomly divided into two groups: the model group (n = 12) received oral administration of normal saline (10 mL/kg) and the agent-treated group (n = 12) received oral treatment with 30 mg/kg FA (L-012-171216, 98.83% purity, Chengdu Herbpurify Co., Ltd., Chengdu, China) beginning on day 8. After 30-day treatment, behavioral experiments were serially performed. The entire treatment protocol lasted for 42 days. Blood samples were collected from the caudal vein. After euthanasia via CO2 inhalation, organs including the brain, liver, spleen, and kidney were collected for further analysis.

Male 6-month-old senescence-resistant R1 (SAMR1) and SAMP8 mice (weight, 28-35 g) were purchased from Beijing SPF Biotechnology. First, mice were placed in the center of an empty testing arena (40 x 40 x 40 cm) and allowed to move freely for adaptation. Next, in the training stage, two similar objects were presented in the testing arena and mice were allowed to explore for 10 min, for 3 consecutive days. On day 4, one of the two familiar objects was replaced by a new object. The time of exploring a novel object or familiar object in 10 min was recorded.

SAMP8 mice were employed as an AD model and were treated with salidroside for 12 weeks. Behavioral tests, immunohistochemistry, HE and Nissl staining, immunofluorescence, transmission electron microscopy, quantitative proteomics, bioinformatic analysis, flow cytometry, iron staining,western blotting, andmolecular dockingwere performed.

B6.1291-Nfe2l2tm1Ywk/J (Nrf2-/-mice, 017009)and wild-type C57BL/6 were originally from the Jackson Laboratory. Grouping and administration were started when weighing approximately 28-33 g. All mice were housed in a laboratory environment with free access to adequate food and water under a 12 h/12 h light/dark cycle at 22 ± 1 and 55 ± 5% humidity. All procedures conformed to the protocols of the Animal Welfare Commission and Ethical Committee of Southern Medical University. The Nrf2-/- mice were identified by genotyping as shown in Fig.1B. WT and Nrf2-/- mice were randomly assigned to 32 groups (3 groups for WT mice and 3 groups for Nrf2-/- mice) as follows: a sham group, sham + Ab1-42 group, and Salidroside + Ab1-42 group.

B6.1291-Nfe2l2tm1Ywk/J (Nrf2-/-mice, 017009)and wild-type C57BL/6 were originally from the Jackson Laboratory. Grouping and administration were started when weighing approximately 28-33 g. All mice were housed in a laboratory environment with free access to adequate food and water under a 12 h/12 h light/dark cycle at 22 ± 1 and 55 ± 5% humidity. All procedures conformed to the protocols of the Animal Welfare Commission and Ethical Committee of Southern Medical University. The Nrf2-/- mice were identified by genotyping as shown in Fig.1B. WT and Nrf2-/- mice were randomly assigned to 32 groups (3 groups for WT mice and 3 groups for Nrf2-/- mice) as follows: a sham group, sham + Ab1-42 group, and Salidroside + Ab1-42 group.

OABL (20 mg/kg per day) dissolved in water with 10% ethanol and 10% Tween 80 was administrated to 6-month-old WT and 5xFAD mice for 3 weeks. WT+OABL and 5xFAD+OABL groups were treated by an intraperitoneal (i.p.) injection of OABL as the above-mentioned. OABL were dissolved in 10% ethanol, 10% Tween 80 and distilled water (according to 0.1% w/vol), and this solution of 10% ethanol, 10% Tween 80, and 80% distilled water was used as the vehicle. Mice from WT+Vehicle group and 5xFAD+Vehicle group were injected with the vehicle. Additional animal tests were conducted afteri.p.injection.