Song Juxian/Tang Chunzhi’s collaborative team discovered a new mechanism for electro-acupuncture (electro-acupuncture) to alleviate the pathology of Alzheimer’s disease and enhance cognitive function

And explore the mysteries of neuroscience with rigorous academic and logical thinking.
Written by Wang Sizhen, edited by Wang Sizhen.
Alzheimer's disease (AD) is the most common neurodegenerative disease.

Senile plaques formed by β-amyloid (Aβ) and neurofibrillary tangles formed by tau protein are two well-known pathological features of AD.

There are still no drugs that can effectively treat AD.

 The autophagy-lysosome pathway is a cellular process that degrades misfolded, aggregated proteins and damaged organelles through lysosomes.
This process is precisely regulated by a variety of signaling pathways and factors.
Among them, the transcription factor EB (TFEB for short) ) Is a major regulator and positively regulates the autophagy-lysosome pathway [1-2].

In the process of many neurodegenerative diseases such as AD, the function of the autophagy-lysosomal pathway and TFEB is impaired [3-4], which suggests that targeting TFEB may be a potential strategy for the prevention and treatment of AD.

 In TCM treatment, acupuncture therapy (acupuncture therapy) and electroacupuncture therapy (electroacupuncture therapy) are commonly used auxiliary therapies for various neurodegenerative diseases [5].

Clinical studies have shown that acupuncture therapy can improve the cognitive function and other clinical conditions of AD patients without obvious side effects [6-7].

However, the curative effect of acupuncture or electroacupuncture on AD animal models and its underlying mechanism need to be studied in depth.

 "Three-needle Acupuncture for Intelligence", namely the middle Shenting acupoint GV24 (belonging to the Dumai acupoint) and the Benshen acupoint GB13 (belonging to the foot Shaoyang gall bladder meridian) (Figure 2), It is a commonly used acupuncture therapy for cognitive-related diseases in southern my country [8].

In addition, "Three-needle Electroacupuncture for Intelligence" (Figure 2), referred to as TNEA, can also enhance the cognitive function of rats [9].

 On February 23, 2021, Ju-xian Song and Chunzhi Tang from the School of Acupuncture and Rehabilitation of Guangzhou University of Traditional Chinese Medicine published a titled “Electroacupuncture ameliorates beta-amyloid pathology” in the internationally renowned journal “Autophagy”.
and cognitive impairment in Alzheimer disease via a novel mechanism involving activation of TFEB (transcription factor EB)" the latest research paper.

The paper revealed that electro-acupuncture (electro-acupuncture) can reduce Aβ pathology in AD models and improve cognitive function by activating TFEB.

The first author of the article is Zheng Xiaoyan.

First, the author performed TNEA operation and sham operation (sham) on 5.
5-month-old 5x FAD mice, and then applied Morris water maze and fear conditioning two behavioral tests to evaluate the spatial learning and memory ability and contextuality of the mice.
Fear memory ability (Figure 1-2).

The results show.

Compared with the sham operation group, the spatial learning memory and situational fear memory of the mice in the TNEA experimental group have been significantly improved, and this improvement in memory function is consistent with the amyloid precursor protein in the prefrontal cortex and hippocampus of the mice caused by TNEA ( APP) pathology is related to the decrease of Aβ pathology.

In other words, TNEA can promote the degradation of APP and Aβ, thereby enhancing memory.

Neuroinflammation is also a common pathological feature of AD.

Here, the authors found that TNEA inhibits the activation of microglia in the brains of AD mice, which prevents the occurrence of neuroinflammation.

Figure 1 Experimental procedure (EA: electroacupuncture; MWM: Morris water maze test; FC: fear conditioning test; WB: western blot; IHC: immunohistochemistry) (picture quoted from: X.
Zheng, et al.
( 2021), Autophagy) Figure 2 "Yizhi three-needle electroacupuncture", namely TNEA (picture quoted from: X.
Zheng, et al.
(2021), Autophagy) Continuous induction of autophagy will cause damage to the tide of autophagy.
There are also defects in lysosomal clearance in AD patients and mice [10-11].

It has been reported that APP and Aβ can be degraded through the autophagy-lysosome pathway mediated by TFEB [13].

Autophagy lysosomes, also called lysosomes, are formed from the fusion of primary lysosomes and autophagosomes.

The authors found that in AD mice, autophagosomes cannot be converted to autophagolysosomes normally, and TNEA treatment can restore their normal conversion; although TNEA treatment does not affect the induction (or induction) of autophagy, it can be obviously It activates TFEB and promotes the production of lysosomes, reducing defective lysosomes associated with Aβ plaques, thereby degrading APP and Aβ.

 So, is this TNEA-mediated degradation of APP and Aβ closely related to the autophagy-lysosome pathway? Experiments such as immunofluorescence, immunohistochemistry and western blotting showed that in the mouse brain, TNEA treatment can restore autophagosomes' recognition of autophagic cargo or substrates and enhance their degradation; TNEA-induced lysosomal activity It is necessary for the degradation of APP and Aβ and memory improvement, and TFEB is also necessary for TNEA-induced degradation of the hydroxyl terminal (ie C-terminal) part of APP and memory improvement.

 At the end of the article, experiments show that under the treatment of mouse TNEA, the activity or phosphorylation level of some kinases upstream of the TFEB pathway (such as MTORC1, MAPK1, AKT, etc.
) is significantly reduced, that is, TNEA may inhibit the kinase upstream of TFEB.

In other words, TNEA may activate the phosphorylation and nuclear transport of TFEB by regulating the activity of some kinases upstream of TFEB, improve the autophagy-lysosome pathway, degrade APP and Aβ, etc.
, play a neuroprotective effect, and increase cognitive function.
. Figure 3 Research summary diagram (CTFs: the hydroxyl end (ie C-terminal) part of APP) (picture quoted from: X.
Zheng, et al.
(2021), Autophagy) Conclusion and discussion of the article "Acupuncture electro-acupuncture", or "Yizhi three-needle electro-acupuncture", namely TNEA, has a cognitive enhancement effect in an AD animal model (Figure 3).

TNEA induces the degradation of full-length and C-terminal APP and Aβ, and inhibits the activation of glial cells in the prefrontal cortex and hippocampus, preventing the occurrence of neuroinflammation; in terms of mechanism, TNEA activates downstream TFEB by inhibiting the AKT-MAPK1-MTORC1 pathway to improve The autophagy-lysosomal pathway in the brain degrades APP and Aβ, alleviates neurotoxicity, and ultimately exerts a neuroprotective effect and increases cognitive function (Figure 3).

 Of course, the study has some unanswered questions.

(1) Although studies have shown the possible mechanism of TNEA-induced TFEB activation, more evidence is needed to verify this possibility, such as overexpression (or increase) of the activity of these kinases in specific brain regions; (2), TFE3 is another transcription factor with similar functions to TFEB [14], so can TNEA also activate TFE3? In other words, does TNEA specifically activate TFEB? (3) Will electroacupuncture at other different acupoints specifically act on TFEB or TFE3, or act synergistically on both, so as to play a neuroprotective effect in neurodegenerative diseases such as AD? In general, the study shows that "three-needle electroacupuncture" (TNEA) is a promising treatment or a potential method for adjuvant treatment of AD (Figure 3).

Original link: https://doi.
org/10.
1080/15548627.
2021.
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TFEB links autophagy to lysosomal biogenesis.
Science.
2011;332(6036):1429–1433.
【2】Sardiello M, Palmieri M, di Ronza A, et al.
A gene network regulating lysosomal biogenesis and function.
Science.
2009;325 (5939):473–477.
[3] Boland B, Yu WH, Corti O, et al.
Promoting the clearance of neurotoxic proteins in neurodegenerative disorders of ageing.
NatRev Drug Discov.
2018;17(9):660–688.
[4] Martini-Stoica H, Xu Y, Ballabio A, et al.
The autophagy-lysosomal pathway in neurodegeneration: A TFEB perspective.
Trends Neurosci.
2016;39 (4):221–234.
【5】Guo X, Ma T.
Effects of acupuncture on neurological disease in clinical- and animal-based research.
Front Integr Neurosci.
2019;13:47.
【6】Zhou J, Peng W , Xu M, et al.
The effectiveness and safety of acupuncture for patients with Alzheimer disease: a systematic review and meta-analysis of randomized controlled trials.
Medicine (Baltimore).
2015;94(22):e933.
【7】Park S , Lee JH, Yang EJ.
Effects of acupuncture on Alzheimer's disease in animal-based research.
Evid Based Complement Alternat Med.
2017;2017:6512520.
【8】Sun W, Li M, Lin T, et al.
Effect of acupuncture at 3-points for intelligence on vascular dementia:protocol for a systematic review and meta-analysis of randomized controlled trials.
Medicine (Baltimore).
2018;97(42):e12892.
【9】Cui S, Xu M, Huang J, et al.
Cerebral responses to acupuncture at GV24 and bilateral GB13 in rat models of Alzheimer's disease.
Behav Neurol.
2018;2018:8740284.
【10】Bordi M, Berg MJ, Mohan PS, et al.
Autophagy flux in CA1 neurons of Alzheimer hippocampus: increased induction overburdens failing lysosomes to propel neuritic dystrophy.
Autophagy.
2016;12(12):2467–2483.
[11] Yang C, Cai CZ, Song JX, et al.
NRBF2 is involved in the autophagic degradation process of APP-CTFs in Alzheimer disease models.
Autophagy.
2017 ;13(12):2028-2040.
[12] Xiao Q, Yan P, Ma X, et al.
Neuronal-targeted TFEB accelerates lysosomal degradation of APP, reducing abeta generation andamyloid plaque pathogenesis.
J Neurosci.
2015;35 (35 ): 12137-12151.
[13] Tanida I, Minematsu-Ikeguchi N, Ueno T, et al.
Lysosomal turnover, but not a cellular level, of endogenous LC3 is a marker for autophagy.
Autophagy.
2005;1(2):84–91.
[14 】Raben N, Puertollano R.
TFEB and TFE3: linking lysosomes to cellular adaptation to stress.
Annu Rev Cell Dev Biol.
2016;32:255–278.
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