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Additional file 1: Figure S1. Effects of TNEA and its composing acupoints on the levels of APP/CTFs/Aβ in 5XFAD mice. (A) Representative Western blots showed the levels of full-length APP (FlAPP) and carboxy-terminal fragments (CTFs) in the prefrontal cortex (PFC) of mice from each group. (B) Data are quantified as mean ± SEM (male, n = 5-7). **p0.05) vs. 5xFAD group, analyzed by unpaired t-test or Mann–Whitney U test. (C) Representative Western blots showed the levels of Aβ in the hippocampus (HI) of mice from each group (n =3). The combined quantification data are shown in Fig. 1F. Figure S2. Activation of NLRP3 inflammasome in the hippocampus of 5xFAD mice. (A, C) Representative Western blots showed the levels of phosphorylated (p-)RELA (p65), NLRP3, CASP1 and IL1B in the hippocampi (HI) of 5xFAD mice at the age of 8 months (A) and 13 months (C). (B, D) Data are quantified as mean ± SEM (male, n = 6). *p0.05) vs. WT group, analyzed by unpaired t-test, unpaired t-test with Welch's correction, or Mann–Whitney U test. Figure S3. Negative controls for the IHC of ASC, NLRP3, SQSTM1 and CTSD. The slides from each group were stained with each 1st antibody at the same dilution as performed in Fig. 3 and 4, but without 2nd antibodies; or stained with 2nd antibodies at the same dilution as performed in Fig. 3 and 4, but without 1st antibodies. Images were visualized at the same settings as performed in Fig. 3 and 4. Scale bar: 100 μm. Figure S4. Effects of TNEA and its composing acupoints on TFEB activation in the prefrontal cortex of 5XFAD mice. (A) Representative Western blots showed the levels of phosphorylated (p-) TFEB (S142) in the prefrontal cortex (PFC) of mice from each group. (B) Data are quantified as mean ± SEM (male, n = 5-7). **p0.05) vs. 5xFAD group analyzed by unpaired t-test, unpaired t-test with Welch's correction, or Mann–Whitney U test. Figure S5. Effects of the composing acupoints of TNEA on TFE3 activation in the hippocampi of 5xFAD mice. (A) Representative Western blots showed the levels of cytosolic (Cyt) /nuclear (Nuc) levels of TFE3 in the hippocampi (HI) of mice from each group. GAPDH and H3F3A (H3 histone) were used as cytosolic and nuclear loading controls, respectively. (B) Data were quantified as mean ± SEM (male, n=5-7). *p0.05) vs. 5xFAD group analyzed by unpaired t-test. Figure S6. Unprocessed scans of all immunoblots.

Peiming Zhang,1 Jie Zhan,2 Shuting Wang,1 Yuyuan Tang,1 Huishan Chen,1 Yiqiao Wang,1 Xiaojing Wei,1 Hao Wen,3 Ting Pan,4 Ze Chen,1 Chunzhi Tang,1 Nenggui Xu,1 Liming Lu1 1Clinical Research and Big Data Laboratory, South China Research Center for Acupuncture and Moxibustion, Medical College of Acu-Moxi and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou City, Guangdong Province, People’s Republic of China; 2Postdoctoral Research Station, Department of Rehabilitation, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou City, Guangdong Province, People’s Republic of China; 3Department of Neurology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou City, Guangdong Province, People’s Republic of China; 4TCM Department, Foshan Fosun Chancheng Hospital, Foshan City, Guangdong Province, People’s Republic of ChinaCorrespondence: Liming Lu, Clinical Research and Data Center, South China Research Center for Acupuncture and Moxibustion, Medical College of Acu-Moxi and Rehabilitation, Guangzhou University of Chinese Medicine, No. 232, Waihuan East Road, University Town, Xiaoguwei Street, Panyu District, Guangzhou City, Guangdong Province, People’s Republic of China, Tel +8613751779800, Fax +862039358716, Email lulimingleon@126.com Chunzhi Tang, Email jordan664@163.comPurpose: Accumulating research suggests that psychotherapy helps improve abstinence but the difference in the efficacy of multiple psychotherapies in alcohol use disorder (AUD) remains to be explored.Patients and Methods: A systematic search of databases (Pubmed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and EBSCO) for studies (published from inception to April 10th.) of adults diagnosed with AUD accepting psychotherapies was conducted. Studies covering 9 countries and regions. The qualitative analysis pooled 2646 individuals from 34 randomized controlled trials (RCTs) and the networks included 1928 participants (23 RCTs). The outcomes included percentage of days abstinent (PDA), change in drinks per drinking day (change in DDD), and change in craving compared among individuals accepting various psychotherapies. The protocol followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), and was registered on the International Prospective Register of Systematic Reviews (PROSPERO).Results: For the network of PDA, motivational enhancement treatment (MET) (35.44, 11.78 to 59.09, high-certainty) and couple therapy (CT) (28.89, 13.42 to 44.36, moderate-certainty) were significantly different from treatment as usual (TAU) with the surface under the cumulative ranking curve (SUCRA) mean rank 1.9 and 1.9 respectively. TAU+supportive psychotherapy (SP) was better than TAU for the change in DDD in the high-quality direct comparison.Conclusion: The motivational enhancement and the couple therapy show potential amelioration for alcohol abstinence. Additionally, the preferred interventions are different for improving PDA and change in DDD. The evidence network remains to be strengthened.Keywords: alcohol use disorder, psychotherapy, randomized controlled trial, systematic review, network meta-analysis