A Pilot Study on the Repetitive Transcranial Magnetic Stimulation of Aβ and Tau Levels in Rhesus Monkey Cerebrospinal Fluid

Summary

Here, we describe the procedure for a pilot study to explore the effect of repetitive transcranial magnetic stimulation with different frequencies (1 Hz/20 Hz/40 Hz) on Aβ and tau metabolism in rhesus monkey cerebrospinal fluid.

Abstract

Previous studies have demonstrated that a non-invasive light-flickering regime and auditory tone stimulation could affect Aβ and tau metabolism in the brain. As a non-invasive technique, repetitive transcranial magnetic stimulation (rTMS) has been applied for the treatment of neurodegenerative disorders. This study explored the effects of rTMS on Aβ and tau levels in rhesus monkey cerebrospinal fluid (CSF). This is a single-blind, self-controlled study. Three different frequencies (low frequency, 1 Hz; high frequencies, 20 Hz and 40 Hz) of rTMS were used to stimulate the bilateral-dorsolateral prefrontal cortex (DLPFC) of the rhesus monkey. A catheterization method was used to collect CSF. All samples were subjected to liquid chip detection to analyze CSF biomarkers (Aβ₄₂, Aβ₄₂/Aβ₄₀, tTau, pTau). CSF biomarker levels changed with time after stimulation by rTMS. After stimulation, the Aβ₄₂ level in CSF showed an upward trend at all frequencies (1 Hz, 20 Hz, and 40 Hz), with more significant differences for the high-frequencies (p < 0.05) than for the low frequency.

After high-frequency rTMS, the total Tau (tTau) level of CSF immediately increased at the post-rTMS timepoint (p < 0.05) and gradually decreased by 24 h. Moreover, the results showed that the level of phosphorylated Tau (pTau) increased immediately after 40 Hz rTMS (p < 0.05). The ratio of Aβ₄₂/Aβ₄₀ showed an upward trend at 1 Hz and 20 Hz (p < 0.05). There was no significant difference in the tau levels with low-frequency (1 Hz) stimulation. Thus, high-frequencies (20 Hz and 40 Hz) of rTMS may have positive effects on Aβ and tau levels in rhesus monkey CSF, while low-frequency (1 Hz) rTMS can only affect Aβ levels.

Introduction

Amyloid-β (Aβ) and tau are important CSF biomarkers. Aβ consists of 42 amino acids (Aβ_1-42), which is the product of transmembrane amyloid precursor protein (APP) hydrolyzed by β- and γ-secretases¹. Aβ_1-42 may aggregate into extracellular amyloid plaques in the brain because of its solubility characteristics^1,2. Tau is a microtubule-associated protein that is mainly present in axons and is involved in anterograde axonal transport³. Abnormal tau hyperphosphorylation is mainly induced by the imbalance between....

Protocol

All the experiments were performed under the Guidance for the Care and Use of Laboratory Animals, formulated by the Ministry of Science and Technology of the People's Republic of China, as well as the principles of the Basel Declaration. Approval was given by the Animal Care Committee of the Sichuan University West China Hospital (Chengdu, China). Figure 1 shows the single-blind, self-controlled study design used here.

1. rTMS devices

1. Use an 8-shap.......

Discussion

Aβ_1-42, a well-established biomarker of AD, is a CSF core biomarker related to Aβ metabolism and amyloid plaque formation in the brain and has been widely used in clinical trials and the clinic²⁶. Recent studies have shown that the CSF Aβ₄₂/Aβ₄₀ ratio is a better diagnostic biomarker of AD than Aβ₄₂ alone because it is a better indicator of the AD-type pathology^27,28. Tau.......

Materials

Name	Company	Catalog Number	Comments
Anesthesia Puncture Kit for Single Use	Weigao, Shandong, China
CCY-I magnetic field stimulator	YIRUIDE MEDICAL, Wuhan, China
GraphPad Prism version 7.0	GraphPad Software, Inc., San Diego, CA, USA
Human Amyloid Beta and Tau Magnetic Bead Panel	EMD Millipore Corporation, Billerica, MA 01821 USA		liquid chip detection
MILLIPLEX Analyst 5.1	EMD Millipore Corporation, Billerica, MA 01821 USA
Monkey Chair HH-E-1	Brainsight, Cambridge, MA 02140 USA
Zoletil 50	Virbac, France		zolazepam–tiletamine