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).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.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.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.
Glycated haemoglobin (HbA1c) is the most important marker of hyperglycaemia in diabetes mellitus. We show that d-ribose reacts with haemoglobin, thus yielding HbA1c. Using mass spectrometry, we detected glycation of haemoglobin with d-ribose produces 10 carboxylmethyllysines (CMLs). The first-order rate constant of fructosamine formation for d-ribose was approximately 60 times higher than that for d-glucose at the initial stage. Zucker Diabetic Fatty (ZDF) rat, a common model for type 2 diabetes mellitus (T2DM), had high levels of d-ribose and HbA1c, accompanied by a decrease of transketolase (TK) in the liver. The administration of benfotiamine, an activator of TK, significantly decreased d-ribose followed by a decline in HbA1c. In clinical investigation, T2DM patients with high HbA1c had a high level of urine d-ribose, though the level of their urine d-glucose was low. That is, d-ribose contributes to HbA1c, which prompts future studies to further explore whether d-ribose plays a role in the pathophysiological mechanism of T2DM.
Diabetic encephalopathy is the brain damage caused by diabetes mellitus and has been recognized and diagnosed in both type 1 and type 2 diabetes mellitus (T1DM and T2DM, respectively). Although many mechanisms have been proposed for diabetic encephalopathy in type 2 diabetes mellitus, the risk factors for cognitive impairment in T1DM are less clear. Here, T1DM patients had abnormally high D-ribose levels in both urine and serum. In streptozotocin-induced T1DM rats, blood and urine D-ribose levels were also significantly increased, accompanied by spatial cognitive impairment in Y maze and Morris water maze assays. Furthermore, advanced glycation end product (AGE) formation, Tau hyperphosphorylation and neuronal death in the hippocampal CA4/DG region were detected in T1DM rats. The expression and activity of transketolase, an important enzyme in the pentose shunt, were decreased, indicating that transketolase may control D-ribose metabolism in T1DM. This assumption was confirmed by the activation of transketolase with benfotiamine. Decreased D-ribose levels; reduced AGE accumulation, Tau hyperphosphorylation, and neuronal death; and improved cognitive ability in T1DM rats were shown after benfotiamine administration. Our work suggests that D-ribose plays a crucial role in the cognitive impairment in T1DM and may provide a novel target for treating diabetic encephalopathy.Funding: This work was supported by grants from Natural Scientific Foundation of China NSFC (31670805), National Key Research and Development Program of China (2016YFC1305900; 2016YFC1306300), Beijing Municipal Science and Technology Project (Z161100000217141 and Z161100000216137), and Youth Innovation Promotion Association CAS (2017132). Declaration of Interest: All authors declared no competing interests in this study.Ethical Approval: The handling of rats and experimental procedures have been approved by the Animal Welfare and Research Ethics Committee of the Institute of Biophysics, Chinese Academy of Sciences (Permit Number: SYXK2016-32).
d-Ribose is active in glycation and rapidly produces advanced glycation end products, leading to cell death and to cognitive impairment in mice. Glycated serum protein (GSP) is a relatively short-term biomarker for glycemic control in diabetes mellitus. However, whether d-ribose is related to GSP is unclear. The aim of this work was to identify the contribution of d-ribose to GSP compared to d-glucose. Here, we showed that the yield of glycated human serum albumin with d-ribose was at least two-fold higher than that with d-glucose in a 2-week incubation. The glycation of human serum albumin (HSA) with d-ribose was much faster than that with d-glucose, as determined by monitoring changes in the fluorescent intensity of glycation products with time. Liquid chromatography-mass spectrometry/mass spectrometry revealed that 17 and 7 lysine residues on HSA were glycated in the presence of d-ribose and d-glucose, respectively, even when the concentration ratio [d-ribose]/[d-glucose] was 1/50. The intraperitoneal injection of d-ribose significantly increased the GSP levels in Sprague Dawley rats, but the injection of d-glucose did not. The level of d-ribose was more positively associated with GSP than the level of d-glucose in streptozotocin-treated rats. In diabetic patients, the levels of both d-ribose and d-glucose were closely related to the level of GSP. Together, these in vitro and in vivo findings indicated that d-ribose is an important contributor to the glycation of serum protein, compared to d-glucose. To assess GSP levels in diabetes mellitus, we should consider the contribution from d-ribose, which plays a nonnegligible role.
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