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

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.

The Interstitial System of the Brain in Health and Disease

“…Changes in the ISS have also been reported in other diseases, such as Parkinson's disease [116], multiple sclerosis [117,118], and epilepsy [17,119]. Moreover, another study in a mouse model of AD by Yue and associates suggested that the destruction of beta-amyloid deposits in the ECS using a light-emitting diode with red light facilitated not only the recovery of ISF drainage but also rescued cognitive function [15]. This study suggested a new avenue for treating AD by targeting beta-amyloid in the ISS.…”

“…Significant transformations ensue in ISS during the development of the brain due to events such as neurogenesis, neuronal migration and differentiation, expansion of dendritic tree, synaptogenesis, gliogenesis, synaptic stripping by microglia, and myelination [1,[5][6][7][8][9][10]. The geometry of the brain ISS also undergoes modification in aging due to the loss of synapses, neurons, dendritic regression, changes in morphology and numbers of glia, senoinflammation, and deposition of amyloid plaques [11][12][13][14][15]. In conditions such as epilepsy, the synchronized firing of a population of neurons may considerably change the geometry of ISS as well as the ISF drainage [16].…”

Therapeutic Approaches for Alzheimer’s Disease: New Perspectives

“…Yue et al [33] used APP/PS1 AD model mice treated, APP/PS1 control mice and healthy C57BL/6 mice as a negative control. The treatment was with photobiomodulation by LED 630 nm with application of 40 minutes and light intensity of 0.55 mW/cm2 in the skull and abdomen 5 days a week for 2 months.…”

Current Techniques for Investigating the Brain Extracellular Space

“…More recently, MRI was applied to show that the presence of β-amyloid in the APP/PS1 Alzheimer's disease mouse model was associated with reduced perivascular ISF flow and glymphatic system function. Notably, this effect could be effectively reversed through controlled heating of the brain tissue by transcranial illumination with red light over a period of 2 months, and this was further associated with rescue of impaired spatial learning (Yue et al, 2019).…”