Angiogenesis and glial responses after near-infrared light attenuates Aβ burden and alleviates cognitive impairments in APP/PS1 mice

Abstract

Alzheimer's disease (AD), a chronic debilitating neurodegenerative disease, is associated with loss of motivation, memory and spatial learning difficulties, as well as language disorders [1]. The pathology of AD is poorly understood. Nevertheless, it is widely believed that the amyloid-β (Aβ)-containing senile plaques is one of the neuropathological hallmarks of AD [2]. Much of this work centered on the biosynthesis of Aβ and factors that influence its production and deposition. Aβ is derived from the regulated intracellular proteolysis of amyloid precursor protein (APP), which is hydrolyzed by the sequential action of the γ- and β-secretases. Normally Aβ peptides contain 39 to 43 amino acids. A number of studies have shown that mutations in the APP gene or in presenilins result in increased β-secretase cleavage and production of both Aβ1-40 and Aβ1-42, which are the major peptides associated with AD plaque formation via aggregation[3]. “The amyloid hypothesis” suggests that the accumulation of Aβ peptides serves as the central event triggering neuron degeneration [4]. Plaque reduction is seen as an indicator of effective therapies.
In 1903, the Danish Niels Finsen won the third Nobel Prize in Physiology and Medicine for the treatment of lupus erythematosus with red light, and since then opened a new chapter of light therapy. The biological effects of low-level lasers on tissue or body were first illustrated by Hungarian physician Endre Mester. In 1967, Mester et al. discovered that the ruby laser (694 nm) could promote hair regeneration and wound healing in mice[5]. It opened a new way in the medical field and developed into "low-dose laser therapy", also known as low-level laser treatment. It refers to irradiate tissue or body with the low-level laser, resulting in not irreversible damage but a series of physiological and biochemical responses to regulate tissues or the body, ultimately ameliorating or curing the diseases[6]. Biological effects of NIR light include wound healing, pain reduction, and alleviation of oral mucositis [7, 8]. Effects such as cytoprotection, cellular proliferation and growth factor release have also been reported [9]. Accumulating studies have explored the effect of light on brain diseases, such as AD [10-15], Parkinson’s disease [16-18], depression [19, 20], stroke [21-23] and traumatic brain injury [24-26]. Low power laser irradiation can rescue neurons loss and dendritic atrophy via upregulation of BDNF in both Aβ-treated hippocampal neurons and cultured APP/PS1 mouse hippocampal neurons [27]. The 808-nm laser can also attenuate Aβ-induced reactive gliosis and proinflammatory cytokines production in the hippocampal CA1 region of the rat injected with Aβ1-42. In addition, PBM ameliorates Aβ-induced oxidative stress by suppressing glucose-6-phosphate dehydrogenase and nicotinamide adenine dinucleotide phosphate oxidase activity [28].
Although many studies have explored the effects of PBM on Aβ-mediated neuronal dysfunction, glial activation, inflammation and oxidative stress. Few studies have explored the mechanisms of PBM on the Aβ clearance. Degradation of cerebral Aβ via efflux across the blood-brain barrier (BBB) into the circulation, and uptake by macrophages, microglia and astrocyte phagocytosis are two main mechanisms of cerebral Aβ clearance[29]. Here, we hypothesized that NIR light could reduce the Aβ burden in the brain of APP/PS1 mice by activating glial responses and promoting cerebral angiogenesis to improve memory and cognitive deficits. To test this, we studied the biological responses of the cerebral vessel and glial cells in the APP/PS1 mice to the NIR light at different pathological progression and its effects on the Aβ clearance. For light treatment, the mice in light groups were placed in the light device and received irradiation of 6 minutes per day for consecutive 60 days, with a wavelength between 1040 nm and 1090 nm. At the last 10 days of irradiation treatment, we tested the memory and learning ability of all mice via behavioral tests. Following the behavioral experiments, mice were humanely sacrificed and prepared to evaluate the effect of NIR light on alterations of glial cells and vessels.
Our results showed that NIR light significantly improved the performance of behavior tests in mice at 12 months old, as well as decreased the Aβ burden of AD mice at different pathological progression. The results suggested that NIR light promoted angiogenesis in the cortex through different VEGF signaling pathways which changed with pathological progression. The vessel density was also positively correlated with the clearance of Aβ deposition, indicating that PBM could reduce Aβ burden via increase cerebral vessel density. Likewise, the microglia and astrocyte in the cortex had unique responses to NIR light. In mice at 6 months old, alteration of microglia morphology was observed, suggesting the increase in Aβ phagocytosis of mice in light group. Meanwhile, there was also a significant decrease in reactive astrocyte. In mice at 12 months old, microglia displayed no differences in morphology among groups, while light recruited more microglia around Aβ which contributed to the clearance of Aβ in the brain. Finally, we also found out that NIR light significantly reduced neurodegeneration in the CA1 region of mice at 12M, which was critical to learning and memory. Overall, our findings suggest that NIR light could reduce cerebral Aβ levels and Aβ-mediated neurotoxicity of APP/PS1 mice through the promotion of angiogenesis and activation of microglia and astrocyte in the brain. It provides new insights into the clinical application of NIR on treating AD.


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Speaker

Xunbin Wei
Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University
China

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