Far infrared light irradiation enhances Aβ clearance via increased exocytotic microglial ATP and ameliorates cognitive deficit in Alzheimer’s disease-like mice

Abstract

Background Exposure to sunlight may decrease the risk of developing Alzheimer’s disease (AD), and visible and near infrared light have been proposed as a possible therapeutic strategy for AD. Here, we investigated the effects of the visible, near infrared and far infrared (FIR) light on the cognitive ability of AD mice, and found that FIR light also showed potential in the improvement of cognitive dysfunction in AD. However, the related mechanism remains to be elucidated. Methods Morris water maze was used to evaluate the cognitive ability of APPswe/PSEN1dE9 double-transgenic AD mice after light treatment. Western blot was carried out to detect the expression of protein involved in synaptic function and amyloid-β (Aβ) production. The protein amount of interleukin (IL)-1β, IL-6, Aβ1-40 and Aβ1-42 were determined using enzyme-linked immunosorbent assay. The mRNA level of receptors was performed using real-time quantitative polymerase chain reaction. Immunostaining was performed to characterize the Aβ burden and microglial Aβ phagocytosis in the brain of AD mice. The Aβ phagocytosis of primary cultured microglia and BV2 were assessed by flow cytometry. The energy metabolism changes were evaluated using related assay kits, including adenosine triphosphate (ATP), lactate content, mitochondrial respiratory chain complex enzymatic activity and oxidized/reduced nicotinamide adenine dinucleotide assay kits. Results Our results showed that FIR light reduced Aβ burden, a hallmark of AD neuropathology, alleviated neuroinflammation, restored the expression of the presynaptic protein synaptophysin, and ameliorated learning and memory impairment in the AD mice. FIR light enhanced mitochondrial oxidative phosphorylation pathway to increase ATP production. This increased intracellular ATP promoted the extracellular ATP release from microglia stimulated by Aβ, leading to the enhanced Aβ phagocytosis through phosphoinositide 3-kinase/mammalian target of rapamycin pathways for Aβ clearance. Conclusions Our findings have uncovered a previously unappreciated function of FIR light in inducing microglial phagocytosis to clean Aβ, which may be the mechanisms for FIR light to improve cognitive dysfunction in AD mice. These results suggest that FIR light treatment is a potential therapeutic strategy for AD.

Downregulation of miR-181c-5p in Alzheimer’s disease weakens the response of microglia to Aβ phagocytosis

“…As AD progresses, microglial cells experience an age-related reduction in microglial capacity to interact with Aβ 46 . With aging, activated microglial cells ineffectively eliminate Aβ and the release of proinflammatory cytokines is elevated 47 .…”

Photobiomodulation in Alzheimer’s Disease—A Complementary Method to State-of-the-Art Pharmaceutical Formulations and Nanomedicine?

“…Transcranial or intranasal PBM for brain stimulation with R and NIR light has focused attention on positive outcomes on cognitive functions, the repair of neurodegenerative processes, control of energy metabolism, and adjustment of chronic brain inflammatory processes in AD subjects. Publications of experimental and clinical studies on tPBM in AD and other neurodegenerative disorders and ischemic brain injuries have demonstrated that this modality of therapy stimulates metabolic processes in brain tissue, increases intracellular ATP production and revives neuronal mitochondrial activity; modulates local oxidative stress; favors angiogenesis, capillary and lymphatic revascularization; restores destroyed synapses and generates new synapses; revitalizes the growth of new neural cells and acts as a neuroprotector, thus improving cognitive function and memory [ 282 , 283 , 284 , 285 , 286 , 287 , 288 , 289 , 290 ].…”

Light, Water, and Melatonin: The Synergistic Regulation of Phase Separation in Dementia

“…Similarly, photobiomodulation employing visible red light (670 nm), non-visible near infrared (NIR, 800–1090 nm), and even far infrared (FIR, 3–25 µm) show encouraging results in the attenuation of symptoms associated with dementia including a reduction in Aβ deposition, size and number of plaque and fibril formation, clearance of misfolded proteins, increased ATP production and reduced ROS production, improved executive and cognitive functions, processing speed, memory performance, mood, energy, and sleep [ 207 , 208 , 209 , 210 , 211 , 212 , 213 , 214 , 215 , 216 , 217 ] ( Table 1 ). The proposal that red and near-infrared wavelengths may promote melatonin synthesis in mitochondria via the pathway involving nitric oxide and enhanced activity of soluble adenylyl cyclase further bolsters the synergistic relationship between light and melatonin [ 218 , 219 ].…”

“…The ability to increase adenosine triphosphate (ATP) production in mitochondria is one of the most widely accepted mechanisms behind the effectiveness of photobiomodulation in dementia and other health challenges [ 211 , 217 , 220 , 221 , 222 ]. The fact that both infrared light and melatonin increase ATP production, and the adenosine moiety of ATP which is structurally similar to melatonin is capable of solubilizing protein aggregation point to the existence of a most unexpected, dynamic relationship between NIR light and melatonin that is inextricably connected to the regulation of hydrogen bonds, viscosity, protein hydration, and protein aggregation ( Figure 1 ).…”