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

Introduction: Pharmacological therapies to treat Alzheimer's disease (AD) targeting A beta have failed for over 100 years. Low levels of laser light can disassemble A beta. In this study, we investigated the mechanisms that A beta-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 A beta-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 similar to 49% penetration ratio into the brains. For the molecular mechanisms, A beta could induce formaldehyde (FA) accumulation by inactivating FA dehydrogenase. Unexpectedly, in turn, FA accelerated A beta deposition in the ECS. However, LED-RL treatment not only directly destroyed A beta assembly in vitro and in vivo but also activated FA dehydrogenase to degrade FA and attenuated FA-facilitated A beta aggregation. Subsequently, LED-RL markedly smashed A beta deposition in the ECS, recovered the flow of ISF, and rescued cognitive functions in AD mice. Discussion: A beta-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 A beta-blocked ECS and suggests that it is a promising noninvasive approach to treat AD. (C) 2019 The Authors. Published by Elsevier Inc. on behalf of the Alzheimer's Association.