Hyperphosphorylation of tau occurs in preclinical and clinical stages of Alzheimer's disease (AD), and hyperphosphorylated tau is the main constituent of the paired helical filaments in the brains of mild cognitive impairment and AD patients. While m

Cancer-associated cachexia is a multi-organ weight loss syndrome, especially with a wasting disorder of adipose tissue and skeletal muscle. Small extracellular vesicles (sEVs) serve as emerging messengers to connect primary tumour and metabolic organs to exert systemic regulation. However, whether and how tumour-derived sEVs regulate white adipose tissue (WAT) browning and fat loss is poorly defined. Here, we report breast cancer cell-secreted exosomal miR-204-5p induces hypoxia-inducible factor 1A (HIF1A) in WAT by targeting von Hippel-Lindau (VHL) gene. Elevated HIF1A protein induces the leptin signalling pathway and thereby enhances lipolysis in WAT. Additionally, exogenous VHL expression blocks the effect of exosomal miR-204-5p on WAT browning. Reduced plasma phosphatidyl ethanolamine level is detected in mice lack of cancer-derived miR-204-5p secretion in vivo. Collectively, our study reveals circulating miR-204-5p induces hypoxia-mediated leptin signalling pathway to promote lipolysis and WAT browning, shedding light on both preventive screenings and early intervention for cancer-associated cachexia.

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.