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1. chinaXiv:201605.01517 [pdf]

Ribosylation triggering Alzheimer's disease-like Tau hyperphosphorylation via activation of CaMKII

Wei, Yan; Han, Chanshuai; Wang, Yujing; Wu, Beibei; Su, Tao; Liu, Ying; He, Rongqiao; Wang, Yujing; Wu, Beibei; Liu, Ying; He, Rongqiao
Subjects: Biology >> Biophysics >> Cell Biology

Type 2 diabetes mellitus (T2DM) is regarded as one of the serious risk factors for age-related cognitive impairment; however, a causal link between these two diseases has so far not been established. It was recently discovered that, apart from high D-glucose levels, T2DM patients also display abnormally high concentrations of uric D-ribose. Here, we show for the first time that the administration of D-ribose, the most active glycator among monosaccharides, produces high levels of advanced glycation end products (AGEs) and, importantly, triggers hyperphosphorylation of Tau in the brain of C57BL/6 mouse and neuroblastoma N2a cells. However, the administration of D-glucose showed no significant changes in Tau phosphorylation under the same experimental conditions. Crucially, suppression of AGE formation using an AGEs inhibitor (aminoguanidine) effectively prevents hyperphosphorylation of Tau protein. Further study shows AGEs resulted from ribosylation activate calcium-/calmodulin-dependent protein kinase type II (CaMKII), a key kinase responsible for Tau hyperphosphorylation. These data suggest that there is indeed a mechanistic link between ribosylation and Tau hyperphosphorylation. Targeting ribosylation by inhibiting AGE formation may be a promising therapeutic strategy to prevent Alzheimer's disease-like Tau hyperphosphorylation and diabetic encephalopathies.

submitted time 2016-05-12 Hits2332Downloads1393 Comment 0

2. chinaXiv:201605.01317 [pdf]

Gavage of D-Ribose induces A beta-like deposits, Tau hyperphosphorylation as well as memory loss and anxiety-like behavior in mice

Wu, Beibei; Wei, Yan; Wang, Yujing; Su, Tao; Liu, Ying; He, Rongqiao; He, Rongqiao; He, Rongqiao; Wu, Beibei; Wang, Yujing; Zhou, Lei
Subjects: Biology >> Biophysics >> Oncology

In addition to D-Glucose, D-Ribose is also abnormally elevated in the urine of type 2 diabetic patients, establishing a positive correlation between the concentration of uric D-Ribose and the severity of diabetes. Intraperitoneal injection of D-Ribose causes memory loss and brain inflammation in mice. To simulate a chronic progression of age-related cognitive impairment, we orally administered D-Ribose by gavage at both a low and high dose to 8 week-old male C57BL/6J mice daily for a total of 6 months, followed by behavioral, histological and biochemical analysis. We found that long-term oral administration of D-Ribose impairs spatial learning and memory, accompanied by anxiety-like behavior. Tau was hyperphosphorylated at AT8, S396, S214 and T181 in the brain. A beta-like deposition was also found in the hippocampus for the high dose group. D-Glucose-gavaged mice did not show significant memory loss and anxiety-like behavior under the same experimental conditions. These results demonstrate that a long-term oral administration of D-Ribose not only induces memory loss with anxiety-like behavior, but also elevates A beta-like deposition and Tau hyperphosphorylation, presenting D-Ribose-gavaged mouse as a model for agerelated cognitive impairment and diabetic encephalopathy.

submitted time 2016-05-11 Hits3236Downloads1134 Comment 0

3. chinaXiv:201605.01305 [pdf]

Age-related formaldehyde interferes with DNA methyltransferase function, causing memory loss in Alzheimer's disease

Tong, Zhiqian; Han, Chanshuai; Qiang, Min; Wu, Beibei; Su, Tao; Liu, Ying; He, Rongqiao; Tong, Zhiqian; Wang, Xiaomin; He, Rongqiao; Han, Chanshuai; Qiang, Min; Wu, Beibei; Su, Tao; Wang, Weishan; Lv, Jihui; Zhang, Shouzi; Luo, Wenhong; Li, Hui; Luo, Hongjun
Subjects: Biology >> Biophysics

Hippocampus-related topographic amnesia is the most common symptom of memory disorders in Alzheimer's disease (AD) patients. Recent studies have revealed that experience-mediated DNA methylation, which is regulated by enzymes with DNA methyltransferase (DNMT) activity, is required for the formation of recent memory as well as the maintenance of remote memory. Notably, overexpression of DNMT3a in the hippocampus can reverse spatial memory deficits in aged mice. However, a decline in global DNA methylation was found in the autopsied hippocampi of patients with AD. Exactly, what endogenous factors that affect DNA methylation still remain to be elucidated. Here, we report a marked increase in endogenous formaldehyde levels is associated with a decline in global DNA methylation in the autopsied hippocampus from AD patients. In vitro and in vivo results show that formaldehyde in excess of normal physiological levels reduced global DNA methylation by interfering DNMTs. Interestingly, intrahippocampal injection of excess formaldehyde before spatial learning in healthy adult rats can mimic the learning difficulty of early stage of AD. Moreover, injection of excess formaldehyde after spatial learning can mimic the loss of remote spatial memory observed in late stage of AD. These findings suggest that aging-associated formaldehyde contributes to topographic amnesia in AD patients. (C) 2015 Elsevier Inc. All rights reserved.

submitted time 2016-05-11 Hits1711Downloads1051 Comment 0

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