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.