Alzheimer disease (AD) is the most prevalent neurodegenerative disorder leading to dementia in the elderly. Unfortunately, no cure for AD is available to date. Increasing evidence has proved the roles of misfolded protein aggregation due to impairment of the macroautophagy/autophagy-lysosomal pathway (ALP) in the pathogenesis of AD, and thus making TFEB (transcription factor EB), which orchestrates ALP, as a promising target for treating AD. As a complementary therapy, acupuncture or electroacupuncture (EA) has been commonly used for treating human diseases. Although the beneficial effects of acupuncture for AD have been primarily studied both pre-clinically and clinically, the real efficacy of acupuncture on AD remains inconclusive and the underlying mechanisms are largely unexplored. In this study, we demonstrated the cognitive-enhancing effect of three-needle EA (TNEA) in an animal model of AD with beta-amyloid (Aβ) pathology (5xFAD). TNEA reduced APP (amyloid beta (A4) precursor protein), C-terminal fragments (CTFs) of APP and Aβ load, and inhibited glial cell activation in the prefrontal cortex and hippocampus of 5xFAD. Mechanistically, TNEA activated TFEB via inhibiting the AKT-MAPK1-MTORC1 pathway, thus promoting ALP in the brains. Therefore, TNEA represents a promising acupuncture therapy for AD, via a novel mechanism involving TFEB activation. Abbreviations Aβ: β-amyloid; AD: Alzheimer disease; AIF1/IBA1: allograft inflammatory factor 1; AKT1: thymoma viral proto-oncogene 1; ALP: autophagy-lysosomal pathway; APP: amyloid beta (A4) precursor protein; BACE1: beta-site APP cleaving enzyme 1; CQ: chloroquine; CTFs: C-terminal fragments; CTSD: cathepsin D; EA: electroacupuncture; FC: fear conditioning; GFAP: glial fibrillary acidic protein; HI: hippocampus; LAMP1: lysosomal-associated membrane protein 1; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MAPK1/ERK2: mitogen-activated protein kinase 1; MAPT: microtubule-associated protein tau; MTORC1: mechanistic target of rapamycin kinase complex 1; MWM: Morris water maze; NFT: neurofibrillary tangles; PFC: prefrontal cortex; PSEN1: presenilin 1; SQSTM1/p62: sequestosome 1; TFEB: transcription factor EB; TNEA: three-needle electroacupuncture

Background: Transcutaneous auricular vagus nerve stimulation (taVNS), as a noninvasive intervention, has beneficial effects on major depressive disorder based on clinical observations. However, the potential benefits and clinical role of taVNS in the treatment of major depressive disorder are still uncertain and have not been systematically evaluated. Therefore, we performed a systematic review and meta-analysis to evaluate the effectiveness and safety of taVNS in treating major depressive disorder. Methods: Four electronic databases, namely, Embase, MEDLINE, the Cochrane Library and PsycINFO, were searched for all related trials published through May 1, 2018. We extracted the basic information and data of the included studies and evaluated the methodological quality with the Cochrane risk of bias tool and the nonrandomized studies-of interventions (ROBINS-I) tool. A meta-analysis of the comparative effects was conducted using the Review Manager 5.3 software. Results: A total of 423 citations from the databases were searched, and 4 studies with 222 individuals were included in the meta-analysis. The taVNS technique could decrease 24-item HAMD scores more than the sham intervention (MD: −4.23, 95% CI: −7.15, −1.31; P = .005) and was also more effective in decreasing Self-Rating Depression Scale scores ((MD: −10.34, 95% CI: −13.48, −7.20; P < .00001), Beck Depression Inventory scores (MD: −10.3, 95% CI: −18.1, −2.5; P = .01) and Self-Rating Anxiety Scale scores (MD: −6.57, 95% CI: −9.30, −3.84; P < .00001). However, there was no significant difference in the Hamilton Anxiety Rating Scale scores between the taVNS and sham taVNS groups (MD: −1.12, 95% CI: −2.56, 0.32; P = .13). No obvious adverse effects of taVNS treatment were reported in the included studies. Conclusion: The results of the analysis preliminarily demonstrated that taVNS therapy can effectively ameliorate the symptoms of major depressive disorder, providing an alternative technique for addressing depression. However, more well-designed RCTs with larger sample sizes and follow-ups are needed in future studies to confirm our findings.

Alzheimer disease (AD) is the most common type of dementia with cognitive decline as one of the core symptoms in older adults. Numerous studies have suggested the value of psychosocial interventions to improve cognition in this population, but which one should be preferred are still matters of controversy. Consequently, we aim to compare and rank different psychosocial interventions in the management of mild to moderate AD with cognitive symptoms. We did a network meta-analysis to identify both direct and indirect evidence in relevant studies. We searched MEDLINE, EMBASE, PsycINFO through the OVID database, CENTRAL through the Cochrane Library for clinical randomized controlled trials investigating psychosocial interventions of cognitive symptoms in patients with Alzheimer disease, published up to August 31, 2017. We included trials of home-based exercise(HE), group exercise(GE), walking program(WP), reminiscence therapy(RT), art therapy(AT) or the combination of psychosocial interventions and acetylcholinesterase inhibitor (ChEIs). We extracted the relevant information from these trials with a predefined data extraction sheet and assessed the risk of bias with the Cochrane risk of bias tool. The outcomes investigated were Mini–Mental State Examination (MMSE) and compliance. We did a pair-wise meta-analysis using the fixed-effects model and then did a random-effects network meta-analysis within a Bayesian framework. We deemed 10 trials eligible, including 682 patients and 11 treatments. The quality of included study was rated as low in most comparison with Cochrane tools. Treatment effects from the network meta-analysis showed WP was better than control (SMD 4.89, 95% CI -0.07 to 10.00) while cognitive training and acetylcholinesterase inhibitor (CT + ChEIs) was significantly better than the other treatments, when compared with simple ChEIs treatment, assessed by MMSE. In terms of compliance, the pair-wise meta-analysis indicated that WP and HE are better than GE and AT, while CT + ChEIs, CST + ChEIs are better than other combined interventions. Our study confirmed the effectiveness of psychosocial interventions for improving cognition or slowing down the progression of cognitive impairment in AD patients and recommended several interventions for clinical practice.