Photostimulation of Extravasation of Beta-Amyloid through the Model of Blood-Brain Barrier

Ekaterina Zinchenko,Nikita Navolokin,Dan Zhu,Andrey Terskov,Tatiana Antonova,Juergen Kurths,Maria Klimova,Oxana Semyachkina-Glushkovskaya,Andrey Morgun,Aysel Mamedova,Elena Osipova,Tingting Yu,Ilana Agranovich,Alexander Shirokov,Inna Blokhina,Elizaveta Boytsova

doi:10.3390/electronics9061056

Abstract

Alzheimer’s disease (AD) is an incurable pathology associated with progressive decline in memory and cognition. Phototherapy might be a new promising and alternative strategy for the effective treatment of AD, and has been actively discussed over two decades. However, the mechanisms of therapeutic photostimulation (PS) effects on subjects with AD remain poorly understood. The goal of this study was to determine the mechanisms of therapeutic PS effects in beta-amyloid (Aβ)-injected mice. The neurological severity score and the new object recognition tests demonstrate that PS 9 J/cm2 attenuates the memory and neurological deficit in mice with AD. The immunohistochemical assay revealed a decrease in the level of Aβ in the brain and an increase of Aβ in the deep cervical lymph nodes obtained from mice with AD after PS. Using the in vitro model of the blood-brain barrier (BBB), we show a PS-mediated decrease in transendothelial resistance and in the expression of tight junction proteins as well an increase in the BBB permeability to Aβ. These findings suggest that a PS-mediated BBB opening and the activation of the lymphatic clearance of Aβ from the brain might be a crucial mechanism underlying therapeutic effects of PS in mice with AD. These pioneering data open new strategies in the development of non-pharmacological methods for therapy of AD and contribute to a better understanding of the PS effects on the central nervous system.

Highlights

Alzheimer’s disease (AD) is marked by a progressive decline in memory and cognition over decades
In our studies we clearly demonstrate that opening of blood-brain barrier (BBB) causes activation of drainage and clearing functions of meningeal lymphatic vessels (MLVs) [15,16,17], which is a pathway of Aβ clearance [3,11]
Our results uncover a significant neurological deficit in mice with AD compared with sham animals

Summary

Introduction

Alzheimer’s disease (AD) is marked by a progressive decline in memory and cognition over decades. Aβ in AD remains unclear, Aβ plaque clearance has been a key target of numerous clinical trials. The one recent trial linked a significant reduction in Aβ plaque to the stabilization of the cognitive decline after. In our recent pilot study, we proposed transcranialphotostimulation (PS) of clearance of Aβ from the brain via a PS-mediated stimulation along the lymphatic pathway [3]. We showedthat the PS-stimulation of the reduction of Aβ plaque in the brain induced an improvement of memory and neurocognitive deficit in mice with AD [3]. The PS-mediated improvement of memory and cognitive status in rodents with AD has been demonstrated in many other experimental investigations [5,6,7,8]

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