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.

To identify the molecular mechanisms and novel therapeutic agents of late-onset Alzheimer’s disease (AD), we performed integrative network analysis using multiple transcriptomic profiles of human brains. With the hypothesis that AD pathology involves the whole cerebrum, we first identified co-expressed modules across multiple cerebral regions of the aging human brain. Among them, two modules (M3 and M8) consisting of 1,429 protein-coding genes were significantly enriched with AD-correlated genes. Differential expression analysis of microarray, bulk RNA-sequencing (RNA-seq) data revealed the dysregulation of M3 and M8 across different cerebral regions in both normal aging and AD. The cell-type enrichment analysis and differential expression analysis at the single-cell resolution indicated the extensive neuronal vulnerability in AD pathogenesis. Transcriptomic-based drug screening from Connectivity Map proposed Gly-His-Lys acetate salt (GHK) as a potential drug candidate that could probably restore the dysregulated genes of the M3 and M8 network. Pretreatment with GHK showed a neuroprotective effect against amyloid-beta-induced injury in differentiated human neuron-like SH-SY5Y cells. Taken together, our findings uncover a dysregulated network disrupted across multiple cerebral regions in AD and propose pretreatment with GHK as a novel neuroprotective strategy against AD.

Background: Exposure to sunlight may decrease the risk of developing Alzheimer’s disease (AD). However, the wavelength of the light with this therapeutic effect and the related mechanism remain elusive. Failure to clear amyloid-β (Aβ), the main component of amyloid plaque, has been considered as a key risk to cause the development of AD. As the resident immune cell in the brain, microglia is able to carry out Aβ clearance. We hypothesize that a component of sunlight improves AD-related cognitive dysfunction and that this beneficial effect may be via Aβ clearance by microglia. Method: The APP/PS1 mice by 8.5 months of age were exposed to the visible light (λ = 500 nm), near infrared light (λ = 800 nm) and far infrared light (λ = 3 - 25 µm) for 60 min per day. After 5-week treatment with different light, all mice began to be subjected to Morris water maze behavior test under SPF environment. Western blotting was carried out to detect the expression of postsynaptic density-95 protein and synaptophysin in the hippocampus. The protein amount of interleukin (IL)-1β and IL-6 in the cerebral cortex were determined by using ELISA kits. Immunostaining was performed to characterize the Aβ, microglia, cluster of differentiation 68. Under the condition of Aβ existing, primary cultured microglia were treated with light for 2 h before Aβ phagocytosis assay.Results: The APP/PS1 mice with different light (VIS, NIR and FIR) treatments showed a trend of improvement in learning compared to those without light treatment during training stage. Moreover, FIR light-treated APP/PS1 mice had better spatial memory than APP/PS1 mice in the probe test. Simultaneously, FIR light treatment restored synaptophysin protein expression, promoted the recruitment of microglia to Aβ plaques, enhanced the phagocytosis of Aβ, reduced Aβ burden and alleviated neuroinflammation.Conclusions: Taken together, FIR light treatment ameliorates the learning and memory impairment in AD-like mice. Our findings uncovered a previously unappreciated function of FIR light, suggesting that FIR light treatment may be a potential therapeutic strategy for AD.