Improvement of glymphatic\u2013lymphatic drainage of beta-amyloid by focused ultrasound in Alzheimer\u2019s disease model

Youngsun Lee,Eun-Joo Park,Dong Soo Lee,Hyun Kim,Yoori Choi,Seokjun Kwon,Jae Young Lee

doi:10.1038/s41598-020-73151-8

Youngsun Lee, Eun-Joo Park + Show 5 more

Open Access

https://doi.org/10.1038/s41598-020-73151-8

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Abstract

Drainage of parenchymal waste through the lymphatic system maintains brain homeostasis. Age-related changes of glymphatic–lymphatic clearance lead to the accumulation beta-amyloid (Aβ) in dementia models. In this study, focused ultrasound treatment in combination with microbubbles (FUS-MB) improved Aβ drainage in early dementia model mice, 5XFAD. FUS-MB enhanced solute Aβ clearance from brain, but not plaques, to cerebrospinal fluid (CSF) space and then deep cervical lymph node (dCLN). dCLN ligation exaggerated memory impairment and progress of plaque formation and also the beneficial effects of FUS-MB upon Aβ removal through CSF-lymphatic routes. In this ligation model, FUS-MB improved memory despite accumulation of Aβ in CSF. In conclusion, FUS-MB enhances glymphatic–lymphatic clearance of Aβ mainly by increasing brain-to-CSF Aβ drainage. We suggest that FUS-MB can delay dementia progress in early period and benefits of FUS-MB depend on the effect of Aβ disposal through CSF-lymphatics.

Highlights

Drainage of parenchymal waste through the lymphatic system maintains brain homeostasis
Immunohistochemistry of Aβ on the serial sections of the entire brain of mice treated with focused ultrasound treatment in combination with microbubbles (FUS-MB) showed the reduction of total area of Aβ deposits in brain region not directly targeted by Focused ultrasound (FUS)-MB (Fig. 1d)
While FUS-MB decreased overall Aβ deposits at 4 months before FUS-MB (Fig. 2b), the Aβ concentration in cerebrospinal fluid (CSF) tended to increase after ligation and increased much more after FUS-MB in 5XFAD mice after deep cervical lymph node (dCLN) ligation (Fig. 3a)

Summary

Introduction

Drainage of parenchymal waste through the lymphatic system maintains brain homeostasis. Interestingly without any drugs delivery, FUS-MB (focused ultrasound treatment in combination with microbubbles) in AD model reduced the deposition of betaamyloid (Aβ) and tau, improved memory, and increased internalization of Aβ in microglia[7,8,9] These effects were mostly considered to be due to BBB opening, while assuming that brain-resident cells disposed on site within the brain all the abnormal proteins such as Aβ or tau[9,10]. Waste disposal from the brain parenchyma to CSF and lymphatics in this investigation This effect might have improved the behavioral impairment in the previous mouse e xperiments[7,8,9,10].

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