Electroacupuncture ameliorates beta-amyloid pathology and cognitive impairment in Alzheimer disease via a novel mechanism involving activation of TFEB (transcription factor EB)

Autophagy. 2021 Nov;17(11):3833-3847. doi: 10.1080/15548627.2021.1886720. Epub 2021 Feb 23.

Abstract

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.

Keywords: Alzheimer disease; autophagy-lysosomal pathway; electroacupuncture; transcription factor EB.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology
  • Alzheimer Disease / therapy*
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism*
  • Brain / metabolism
  • Brain / pathology*
  • Cognitive Dysfunction / metabolism
  • Cognitive Dysfunction / pathology
  • Cognitive Dysfunction / therapy*
  • Disease Models, Animal
  • Electroacupuncture* / methods
  • Female
  • Lysosomes / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Microglia / metabolism
  • Microglia / pathology
  • Morris Water Maze Test

Substances

  • Amyloid beta-Peptides
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Tcfeb protein, mouse

Grants and funding

This study is supported by the following grants: NSFC/82074042 to Ju-Xian Song; NSFC/81804197 to Qingwei Huo; NSFC/81873375 and Scientific Research Team Training Project of GZUCM (No.: 2019KYTD203) to Chunzhi Tang; Key Laboratory of Acupuncture and Moxibustion of Traditional Chinese Medicine in Guangdong (No.: 2012A061400017) and Innovation to strengthen school project of Guangdong provincial education department-national major cultivation project (No.: 2014GKXM031) to Nenggui Xu; and NSFC/81773926, NSFC/81703487, JCYJ20180302174028790, JCYJ20180507184656626, GRF/HKBU12101417, GRF/HKBU12100618, HMRF17182541, HMRF 17182551, HKBU/RC-IRCs/17-18/03 to Min Li.