Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disease with high prevalence rate among the elderly population. A large number of clinical studies have suggested repetitive transcranial magnetic stimulation (rTMS) as a promising non-invasive treatment for patients with mild to moderate AD. However, the underlying cellular and molecular mechanisms remain largely uninvestigated. In the current study, we examined the effect of high frequency rTMS treatment on the cognitive functions and pathological changes in the brains of 4- to 5-month old 5xFAD mice, an early pathological stage with pronounced amyloidopathy and cognitive deficit. Our results showed that rTMS treatment effectively prevented the decline of long-term memories of the 5xFAD mice for novel objects and locations. Importantly, rTMS treatment significantly increased the drainage efficiency of brain clearance pathways, including the glymphatic system in brain parenchyma and the meningeal lymphatics, in the 5xFAD mouse model. Significant reduction of Aβ deposits, suppression of microglia and astrocyte activation, and prevention of decline of neuronal activity as indicated by the elevated c-FOS expression, were observed in the prefrontal cortex and hippocampus of the rTMS-treated 5xFAD mice. Collectively, these findings provide a novel mechanistic insight of rTMS in regulating brain drainage system and β-amyloid clearance in the 5xFAD mouse model, and suggest the potential use of the clearance rate of contrast tracer in cerebrospinal fluid as a prognostic biomarker for the effectiveness of rTMS treatment in AD patients.
Highlights
Alzheimer’s disease (AD) is the most common type of dementia, featured by progressive impairment of cognitive functions across multiple domains including memory, language, emotion, executive ability, and eventually the ability to live independently [60]
We showed that repetitive transcranial magnetic stimulation (rTMS) treatment at early age of 5xFAD mice effectively prevented decline of long-term memories for novel object and location, which was accompanied by enhanced drainage efficiency through brain glymphatic system and meningeal lymphatics, reduction of Amyloid beta (Aβ) deposits, reduced activation of microglia and astrocyte, and prevention of decline of neuronal activity as indicated by increased c-FOS expression in the 5xFAD mouse brains
As the glymphatic system connects to the meningeal lymphatics, to examine whether the accumulated tracer in the medial prefrontal cortex (mPFC) of 5xFAD brains may be due to reduced drainage efficiency of the glymphatic system and meningeal lymphatics, we examined the distribution of tracer in the dura mater where meningeal lymphatics were identified, and in the deep cervical lymph nodes (dCLNs) which connect to meningeal lymphatics [2, 46]
Summary
Alzheimer’s disease (AD) is the most common type of dementia, featured by progressive impairment of cognitive functions across multiple domains including memory, language, emotion, executive ability, and eventually the ability to live independently [60]. Recently discovered/rediscovered brain drainage machinery, the glymphatic system along the cerebral vasculatures in the brain parenchyma and the meningeal lymphatic vessels in the dura mater, have been proposed to play important roles in the clearance of Aβ from the brain, and aging-related impairment of the glymphatic system or the meningeal lymphatics is thought to aggravate Aβ accumulation in the AD brains [14, 29, 49], forming a vicarious feedback cycle to aggravate AD pathological development. Reduced perivascular astrocytic end feet localization of AQP4 and increased astrocyte activation in the aged or traumatic brain injury mouse models have been reported to exacerbate glymphatic pathway dysfunction [25, 28]. Given the complex nature of AD, advance in effective treatments is still lacking and will require the mechanistic elucidation of the disease and the multiple cell types that are involved
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