Improvement of glymphatic–lymphatic drainage of beta-amyloid by focused ultrasound in Alzheimer’s disease model

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.

Localized Modification of Water Molecule Transport After Focused Ultrasound-Induced Blood–Brain Barrier Disruption in Rat Brain

“…Despite the evidence of water clearance by FUS–BBBD ( Meng et al, 2019 ; Lee et al, 2020 ), the water dynamics in the local sonication region have yet to be ascertained. Here, we aimed to explore whether FUS–BBBD could induce local water diffusivity changes, which would provide preliminary support for understanding the underlying mechanisms of waste clearance by FUS–BBBD.…”

“… Meng et al (2019) showed that the MR contrast agent can be delivered to the brain parenchyma, and further observed clearance in the interstitial fluid pathway through the perivenular and subarachnoid spaces, as well as around draining veins. Lee et al (2020) demonstrated that FUS–BBBD enhances the glymphatic clearance of Aβ mainly by increasing brain-to-CSF drainage. This glymphatic dynamic may be related to biological effects induced by mechanical forces; however, the subsequent changes in water dynamics in the local perivascular region are yet to be clearly established ( Burgess et al, 2012 ; Meng et al, 2019 ).…”

“…The reduction of Aβ and tau has also been shown by FUS–BBBD with activation of astrocytes and microglia ( Jordao et al, 2013 ; Leinenga and Götz, 2015 ; Nisbet et al, 2017 ; Pandit et al, 2019 ), which implies the possibility of an impact of FUS–BBBD on waste clearance ( Todd et al, 2020 ). A recent study observed that FUS-induced BBBD might drive interstitial flow in the perivascular region ( Meng et al, 2019 ; Curley et al, 2020 ; Lee et al, 2020 ). Curley et al (2020) developed a non-viral gene delivery approach for transfecting brain tumors using FUS with microbubbles and demonstrated interstitial fluid flow changes in response to BBBD.…”

“…Here, we assumed that FUS-induced BBBD would have an influence on the brain-wide clearance system based on previous evidence ( Meng et al, 2019 ; Curley et al, 2020 ; Lee et al, 2020 ) and aimed to establish subsequent changes in local water dynamics by FUS-induced BBBD. One method for non-invasive measurement of water diffusion is diffusion tensor imaging (DTI), which is a magnetic resonance imaging (MRI) technique that measures the mobility of water molecules in tissues based on its ability to determine the orientation and diffusion characteristics ( Tae et al, 2018 ).…”

Alzheimer’s disease as a syndrome of overloaded amyloidic synaptic tagging in memory networks

“…These enzymes typically have targets other than Aβ so understanding how their regulation fits in to the wider proteome is crucial to understanding their role in AD and their viability as therapeutic targets. In addition to enzymatic degradation, Aβ is also cleared by interstitial fluid drainage and drainage through the glymphatic system (see Jessen et al, 2015;Yoon and Jo, 2012) with recent studies in the 5XFAD mouse model interestingly showing this can be promoted by ultrasound (Lee et al, 2020). AD-sufferers exhibit reduced CSF levels of Aβ42, an observation that confers this measure as a predictive biomarker, albeit not as well as the ratio of Aβ42 to Aβ40 (Hansson et al, 2019;Holtzman, 2011).…”