High‐frequency transcranial magnetic stimulation protects APP/PS1 mice against Alzheimer’s disease progress by reducing APOE and enhancing autophagy

Abstract

Introduction The repetitive transcranial magnetic stimulation (rTMS) has clinically wide application prospect of psychiatry and neuroscience, for its painless, noninvasive, and high efficiency. So far, rTMS has been used in the treatment of Alzheimer's disease (AD) but the underlying mechanism is not clear. Methods and Results The APP/PS1 mice at 3‐month‐old were treated by 5 Hz high‐frequency (HF) rTMS for two weeks. After rTMS treatment, the AD‐like cognitive impairments of APP/PS1 mice were investigated subsequently, and molecular mechanisms underlying was further explored. The study showed that the 2‐week rTMS at 5Hz frequency improved cognitive impairments and AD‐like pathology (including a decrease in p‐Tau, APP, Aβ, and PP2A expression) of APP/PS1 mice. Although BDNF‐TrkB signaling was significantly enhanced, no differences of SYN, PSD95 and p‐AKT were observed in the brain of APP/PS1 mice. On the contrary, the LC3Ⅱ/LC3Ⅰ ratio was elevated with a significant reduction of ApoE and p62 in mice. Conclusions rTMS exerts a potentially protective role in the prevention and treatment of AD by reducing ApoE expression and promoting autophagic flux, which provides a new insight into the mechanism of rTMS.

Repetitive transcranial magnetic stimulation increases the brain’s drainage efficiency in a mouse model of Alzheimer’s disease

“…The reduction of Aβ deposits by rTMS could be mediated by two processes: reduced Aβ production and/or facilitated Aβ clearance. Indeed, consistent with previous reports [ 8 , 47 , 65 ], we observed a significant reduction in the intraneuronal Aβ levels in the mPFC, dHC and S1 cortex, indicating that rTMS treatment suppressed Aβ production (Fig. 2 c).…”

“…Our findings are in agreement with previous reports, that rTMS treatment resulted in the reduction of Aβ deposit in the hippocampus of AD mouse models [ 8 , 47 , 65 ]. Although previous studies have shown that rTMS may suppress the expression of APP and APP cleavage enzyme, β-secretase 1 (BACE1), therefore reduce the production and processing of Aβ in the AD mouse brains [ 27 ], however, merely reducing Aβ production may not be sufficient for the pathological improvement and cognitive benefits observed in rTMS-treated AD animal models and patients.…”

“…Furthermore, a meta-analysis on randomized-controlled clinical trials suggested that high frequency rTMS treatment that targeted multiple brain regions was more effective than targeting any single region for cognitive improvement in AD patients [ 41 ]. A few studies have shown that rTMS treatment reduces the production of Aβ peptide, recovers neuronal plasticity and reduces neuronal apoptosis in AD mouse models [ 7 , 8 , 27 , 62 ]. Despite that, the cellular mechanisms by which rTMS improves cognitive functions and how rTMS may affect Aβ clearance in the AD brains remain under-investigated.…”

Targeting autophagy in neurodegenerative diseases: From molecular mechanisms to clinical therapeutics

“…51 Similarly, repetitive transcranial magnetic stimulation (rTMS) alleviates AD via promoting autophagy and reducing apolipoprotein E (APOE). 52 Furthermore, an in vitro model of AD revealed that β-asarone (derived from Acorus tatarinowii Schott) effectively counters those proteins implicated in AD pathogenesis including amyloid-beta precursor protein (APP), presenilin-1 (PSEN1/PS-1), beta-secretase 1 (BACE1), and Aβ via potentiating autophagy, which is demonstrated by LC3-II and BECN1 upregulation. 53 Moreover, in the SAMP8 mouse AD model, treatment with Yishen Huazhuo decoction enhanced Aβ removal via upregulation of BECN1 and downregulation of MTORC1 and promoted autophagosome formation, resulting in enhanced autophagy.…”

Activate or Inhibit? Implications of Autophagy Modulation as a Therapeutic Strategy for Alzheimer’s Disease

“…However, identifying the specific autophagy failure is imperative to the development of therapeutic strategies [129]. Induction of autophagy reduces the levels of both the soluble and aggregated species in AD models and is associated with beneficial effects [130][131][132][133][134][135]. Many autophagy enhancing molecules have been developed [76,77] and their therapeutic effects have been extensively reviewed previously [136,137].…”