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

Xiangpei Yue; Yufei Mei; Yun Zhang; Zheng Tong; Dehua Cui; Jun Yang; Aibo Wang; Rui Wang; Xuechao Fei; Li Ai; Yalan Di; Hongjun Luo; Hui Li; Wenhong Luo; Yu Lu; Rui Li; Chunli Duan; Ge Gao; Hui Yang; Binggui Sun; Rongqiao He; Weihong Song; Hongbin Han; Zhiqian Tong

doi:10.1016/j.trci.2019.09.007

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

Alzheimers Dement (N Y). 2019 Oct 30:5:671-684. doi: 10.1016/j.trci.2019.09.007. eCollection 2019.

Authors

Xiangpei Yue¹, Yufei Mei^{1

2}, Yun Zhang³, Zheng Tong^{4

5}, Dehua Cui⁶, Jun Yang⁶, Aibo Wang⁶, Rui Wang⁶, Xuechao Fei¹, Li Ai¹, Yalan Di¹, Hongjun Luo⁷, Hui Li⁷, Wenhong Luo⁷, Yu Lu⁸, Rui Li⁸, Chunli Duan⁹, Ge Gao⁹, Hui Yang⁹, Binggui Sun², Rongqiao He^{1

10}, Weihong Song³, Hongbin Han⁶, Zhiqian Tong¹

Affiliations

¹ Laboratory of Alzheimer's Optoelectric Therapy, Alzheimer's Disease Center, Beijing Institute for Brain Disorders, Capital Medical University, Beijing, China.
² School of Basic Medical Sciences, Zhejiang University, Hangzhou, China.
³ Department of Psychiatry, Townsend Family Laboratories, The University of British Columbia, Vancouver, Canada.
⁴ School of Engineering, Mechanical Engineering with Renewable Energy. Old College, The University of Edinburgh, Edinburgh, United Kingdom.
⁵ Nanjing University of Aeronautics and Astronautics, Institute of Aeronautics and Astronautics, Aircraft Design and Engineering, Nanjing, China.
⁶ Department of Radiology, Peking University Third Hospital, Key Laboratory of Magnetic Resonance Imaging Equipment and Technique, Beijing, China.
⁷ Central Laboratory, Shantou University Medical College, Guangdong, China.
⁸ Section of Environmental Biomedicine, Hubei Key Laboratory of Genetic Regulation and Integrative Biology, College of Life Sciences, Central China Normal University, Wuhan, China.
⁹ Department of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.
¹⁰ 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.

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.

Keywords: Alzheimer's disease (AD); Amyloid β (Aβ); Extracellular space (ECS); Formaldehyde (FA); Formaldehyde dehydrogenase (FDH); Interstitial fluid (ISF); Red light (RL).