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      New insight into Alzheimer's disease: Light reverses Aβ-obstructed interstitial fluid flow and ameliorates memory decline in APP/PS1 mice

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          Abstract

          Introduction

          Pharmacological therapies to treat Alzheimer's disease (AD) targeting “Aβ” have failed for over 100 years. Low levels of laser light can disassemble Aβ. In this study, we investigated the mechanisms that Aβ-blocked extracellular space (ECS) induces memory disorders in APP/PS1 transgenic mice and addressed whether red light (RL) at 630 nm rescues cognitive decline by reducing Aβ-disturbed flow of interstitial fluid (ISF).

          Methods

          We compared the heating effects on the brains of rats illuminated with laser light at 630, 680, and 810 nm for 40 minutes, respectively. Then, a light-emitting diode with red light at 630 nm (LED-RL) was selected to illuminate AD mice. The changes in the structure of ECS in the cortex were examined by fluorescent double labeling. The volumes of ECS and flow speed of ISF were quantified by magnetic resonance imaging. Spatial memory behaviors in mice were evaluated by the Morris water maze. Then, the brains were sampled for biochemical analysis.

          Results

          RL at 630 nm had the least heating effects than other wavelengths associated with ~49% penetration ratio into the brains. For the molecular mechanisms, Aβ could induce formaldehyde (FA) accumulation by inactivating FA dehydrogenase. Unexpectedly, in turn, FA accelerated Aβ deposition in the ECS. However, LED-RL treatment not only directly destroyed Aβ assembly in vitro and in vivo but also activated FA dehydrogenase to degrade FA and attenuated FA-facilitated Aβ aggregation. Subsequently, LED-RL markedly smashed Aβ deposition in the ECS, recovered the flow of ISF, and rescued cognitive functions in AD mice.

          Discussion

          Aβ-obstructed ISF flow is the direct reason for the failure of the developed medicine delivery from superficial into the deep brain in the treatment of AD. The phototherapy of LED-RL improves memory by reducing Aβ-blocked ECS and suggests that it is a promising noninvasive approach to treat AD.

          Graphical abstract

          Highlights

          • Aβ-inactivated formaldehyde dehydrogenase induces formaldehyde accumulation.

          • Formaldehyde in turn accelerates Aβ deposition in the extracellular space.

          • Red light activates formaldehyde dehydrogenase to degrade formaldehyde.

          • Red light reduces Aβ self-aggregation and formaldehyde-promoted assembly.

          • Red light recovers interstitial fluid flow and alleviates memory deficits.

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          Most cited references 38

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          The dual role of the extracellular matrix in synaptic plasticity and homeostasis.

          Recent studies have deepened our understanding of multiple mechanisms by which extracellular matrix (ECM) molecules regulate various aspects of synaptic plasticity and have strengthened a link between the ECM and learning and memory. New findings also support the view that the ECM is important for homeostatic processes, such as scaling of synaptic responses, metaplasticity and stabilization of synaptic connectivity. Activity-dependent modification of the ECM affects the formation of dendritic filopodia and the growth of dendritic spines. Thus, the ECM has a dual role as a promoter of structural and functional plasticity and as a degradable stabilizer of neural microcircuits. Both of these aspects are likely to be important for mental health.
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            Inhibition of GSK3β-mediated BACE1 expression reduces Alzheimer-associated phenotypes.

            Deposition of amyloid β protein (Aβ) to form neuritic plaques in the brain is the pathological hallmark of Alzheimer's disease (AD). Aβ is generated from sequential cleavages of the β-amyloid precursor protein (APP) by the β- and γ-secretases, and β-site APP-cleaving enzyme 1 (BACE1) is the β-secretase essential for Aβ generation. Previous studies have indicated that glycogen synthase kinase 3 (GSK3) may play a role in APP processing by modulating γ-secretase activity, thereby facilitating Aβ production. There are two highly conserved isoforms of GSK3: GSK3α and GSK3β. We now report that specific inhibition of GSK3β, but not GSK3α, reduced BACE1-mediated cleavage of APP and Aβ production by decreasing BACE1 gene transcription and expression. The regulation of BACE1 gene expression by GSK3β was dependent on NF-κB signaling. Inhibition of GSK3 signaling markedly reduced Aβ deposition and neuritic plaque formation, and rescued memory deficits in the double transgenic AD model mice. These data provide evidence for regulation of BACE1 expression and AD pathogenesis by GSK3β and that inhibition of GSK3 signaling can reduce Aβ neuropathology and alleviate memory deficits in AD model mice. Our study suggests that interventions that specifically target the β-isoform of GSK3 may be a safe and effective approach for treating AD.
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              Light level and duration of exposure determine the impact of self-luminous tablets on melatonin suppression.

              Exposure to light from self-luminous displays may be linked to increased risk for sleep disorders because these devices emit optical radiation at short wavelengths, close to the peak sensitivity of melatonin suppression. Thirteen participants experienced three experimental conditions in a within-subjects design to investigate the impact of self-luminous tablet displays on nocturnal melatonin suppression: 1) tablets-only set to the highest brightness, 2) tablets viewed through clear-lens goggles equipped with blue light-emitting diodes that provided 40 lux of 470-nm light at the cornea, and 3) tablets viewed through orange-tinted glasses (dark control; optical radiation <525 nm ≈ 0). Melatonin suppressions after 1-h and 2-h exposures to tablets viewed with the blue light were significantly greater than zero. Suppression levels after 1-h exposure to the tablets-only were not statistically different than zero; however, this difference reached significance after 2 h. Based on these results, display manufacturers can determine how their products will affect melatonin levels and use model predictions to tune the spectral power distribution of self-luminous devices to increase or to decrease stimulation to the circadian system. Copyright © 2012 Elsevier Ltd and The Ergonomics Society. All rights reserved.
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                Author and article information

                Contributors
                Journal
                Alzheimers Dement (N Y)
                Alzheimers Dement (N Y)
                Alzheimer's & Dementia : Translational Research & Clinical Interventions
                Elsevier
                2352-8737
                30 October 2019
                2019
                30 October 2019
                : 5
                : 671-684
                Affiliations
                [a ]Laboratory of Alzheimer's Optoelectric Therapy, Alzheimer's Disease Center, Beijing Institute for Brain Disorders, Capital Medical University, Beijing, China
                [b ]School of Basic Medical Sciences, Zhejiang University, Hangzhou, China
                [c ]Department of Psychiatry, Townsend Family Laboratories, The University of British Columbia, Vancouver, Canada
                [d ]School of Engineering, Mechanical Engineering with Renewable Energy. Old College, The University of Edinburgh, Edinburgh, United Kingdom
                [e ]Nanjing University of Aeronautics and Astronautics, Institute of Aeronautics and Astronautics, Aircraft Design and Engineering, Nanjing, China
                [f ]Department of Radiology, Peking University Third Hospital, Key Laboratory of Magnetic Resonance Imaging Equipment and Technique, Beijing, China
                [g ]Central Laboratory, Shantou University Medical College, Guangdong, China
                [h ]Section of Environmental Biomedicine, Hubei Key Laboratory of Genetic Regulation and Integrative Biology, College of Life Sciences, Central China Normal University, Wuhan, China
                [i ]Department of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
                [j ]State Key Laboratory of Brain & Cognitive Science, Institute of Biophysics, CAS Key Laboratory of Mental Health, University of Chinese Academy of Sciences (UCAS), Beijing, China
                Author notes
                []Corresponding author. Tel: +86-010-83950362; Fax: +86-010-83950363. tzqbeida@ 123456ccmu.edu.cn
                [∗∗ ]Corresponding author. Tel: 604-822-8019; Fax: 604-822-7981. weihong@ 123456mail.ubc.ca
                [∗∗∗ ]Corresponding author. Tel: +86-010-82266972; Fax: +86-010-82265962. hanhongbin@ 123456bjmu.edu.cn
                [1]

                These authors contributed equally to this work.

                Article
                S2352-8737(19)30067-8
                10.1016/j.trci.2019.09.007
                6838540
                © 2019 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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