D-ribosylation induces cognitive impairment through RAGE-dependent astrocytic inflammation

Abstract

Non-enzymatic glycation of proteins by reducing saccharides for instance D-glucose is an important post-translational modification regulating protein function. Already two centuries ago, D-glucose (Glc) was identified in the urine of diabetic patients. Recently, abnormally high level of D-ribose (Rib) in the urine of type 2 diabetics has been discovered, which is highly active in protein glycation, resulting in the production of advanced glycation end products (AGEs). Accumulation of AGEs leads to altered cellular function, for example AGE accumulation in the nervous system impairs cognitive ability, yet the mechanisms mediating this process for Rib are unknown. Here we found that treatment with Rib accelerated AGE formation in U251 and U87MG astrocytoma cells and in mouse brain, inducing upregulation of receptor for AGEs (RAGE). Astrocytoma cells with elevated levels of RAGE displayed enhanced activity of the proinflammatory nuclear transcription factor kappaB and increased expression of tumor necrosis factor alpha and glial fibrillary acidic protein. Moreover, injection of Rib induced astrocyte activation in mouse hippocampus and impaired spatial learning and memory abilities. These results indicate that mouse spatial cognitive impairment caused by Rib-derived AGEs is correlated with activation of an astrocyte-mediated, RAGE-dependent inflammatory response. This study may provide insights into the mechanism of Rib-involved cognitive impairments and diabetic encephalopathy.

Jiangtang decoction ameliorate diabetic nephropathy through the regulation of PI3K/Akt-mediated NF-κB pathways in KK-Ay mice

“…In addition, the expression of IRS-1, PI3K/Akt, and NF-κB, as well as the histological changes observed in the KK-Ay model group, are consistent with previous reports [3, 24, 36]. The findings of the present study suggest that JTD can relieve DN by down-regulating increased levels of blood glucose, so as to reduce the accumulation of AGEs and RAGE, as well as alleviate inflammation via activation of the PI3K/Akt signaling pathways and inhibiting NF-κB signaling.…”

Maternal immune activation increases seizure susceptibility in juvenile rat offspring

“…Recently, increasing evidence suggests that astrocytes participate actively and importantly in information processing, signal transmission, and regulation of synaptic plasticity [29]. Astrogliosis correlates inversely with cognitive function [30,31], and enhanced GFAP contributes to impaired spatial learning and memory abilities [32]. The precise mechanisms leading to exacerbated seizureinduced spatial learning deficits due to MIA remain unclear.…”

The Impact of Microbiota-Gut-Brain Axis on Diabetic Cognition Impairment

“…Rib exists in all kinds of cells and is a key component of many important biological molecules (Keller et al, 1988). There is a clinical study involving type 2 diabetes patients reported that the urine level of Rib in these patients is abnormally high (Tao et al, 2013), and this elevation participates in cognitive dysfunction in these patients (Han et al, 2014). This finding is further demonstrated by animal experiments that intraperitoneal injection of Rib to mice can significantly increase the plasma glycated proteins and AGEs content, while with less impact on blood sugar (Wei et al, 2012); moreover, this treatment significantly increases brain levels of AGEs, and contributes to learning and memory decline (Han et al, 2011).…”