O -GlcNAc and Neurodegeneration: Biochemical Mechanisms and Potential Roles in Alzheimer\u27s Disease and Beyond

Alzheimer disease (AD) is a growing problem for aging populations worldwide. Despite significant efforts, no therapeutics are available that stop or slow progression of AD, which has driven interest in the basic causes of AD and the search for new therapeutic strategies. Longitudinal studies have clarified that defects in glucose metabolism occur in patients exhibiting Mild Cognitive Impairment (MCI) and glucose hypometabolism is an early pathological change within AD brain. Further, type 2 diabetes mellitus (T2DM) is a strong risk factor for the development of AD. These findings have stimulated interest in the possibility that disrupted glucose regulated signaling within the brain could contribute to the progression of AD. One such process of interest is the addition of O-linked N-acetylglucosamine (O-GlcNAc) residues onto nuclear and cytoplasmic proteins within mammals. O-GlcNAc is notably abundant within brain and is present on hundreds of proteins including several, such as tau and the amyloid precursor protein, which are involved in the pathophysiology AD. The cellular levels of O-GlcNAc are coupled to nutrient availability through the action of just two enzymes. O-GlcNAc transferase (OGT) is the glycosyltransferase that acts to install O-GlcNAc onto proteins and O-GlcNAcase (OGA) is the glycoside hydrolase that acts to remove O-GlcNAc from proteins. Uridine 5′-diphosphate-N-acetylglucosamine (UDP-GlcNAc) is the donor sugar substrate for OGT and its levels vary with cellular glucose availability because it is generated from glucose through the hexosamine biosynthetic pathway (HBSP). Within the brains of AD patients O-GlcNAc levels have been found to be decreased and aggregates of tau appear to lack O-GlcNAc entirely. Accordingly, glucose hypometabolism within the brain may result in disruption of the normal functions of O-GlcNAc within the brain and thereby contribute to downstream neurodegeneration. While this hypothesis remains largely speculative, recent studies using different mouse models of AD have demonstrated the protective benefit of pharmacologically increased brain O-GlcNAc levels. In this review we summarize the state of knowledge in the area of O-GlcNAc as it pertains to AD while also addressing some of the basic biochemical roles of O-GlcNAc and how these might contribute to protecting against AD and other neurodegenerative diseases

Detection of functional state after alcohol consumption by classification and machine learning technics

BIBM 2018, IEEE International Conference on Bioinformatics and Biomedicine, Madrid, ESPAGNE, 03-/12/2018 - 06/12/2018Machine learning (ML) technics have been recently used to detect emotion and predict crash severity. This research work aims at assessing different classifications and machine learning technics in predicting the alcohol consumption and associated functional states. 28 young drivers were tested for a 45 min drive with a blood alcohol concentration (BAC) of 0.0, 0.2 and 0.5g/m. Subjective functional states were analysed using Thayer's scale and NASA-TLX. The physiological parameters (electroencephalogram, electrodermal and cardiac activity) and driver simulators parameters (speed, lateral positioning and wheel steering) were acquired during the three alcohol sessions. Data were analysed on 10s temporal windows without superposition nor gap. Two analyses using classification and ML technics were used: to determine both capacity of the algorithms to detect alcohol consumption (BAC level) and functional states (effort, performance and alertness) from NASA and Thayer's scales. Different algorithms were trained using 10 folds cross validation technics using Weka (University of Waikato, NZ). Using both vehicle and physiological data was beneficial for BAC prediction and ROC area of the top three algorithms were found between 0.62 and 0.72 with higher results for Random Forest (RF) algorithms. In functional states prediction, results were similar for all effort, performance and alertness predictions with ROC area reaching 0.75 for RF. Once algorithm setting optimized, performances for BAC prediction reached 0.73 while were, lower than for functional states prediction with ROC area of 0.91 when pairing data. Such results could help in the strategy for detecting alcohol consumption in drivers

Presenilins Promote the Cellular Uptake of Copper and Zinc and Maintain Copper Chaperone of SOD1-dependent Copper/Zinc Superoxide Dismutase Activity*

Dyshomeostasis of extracellular zinc and copper has been implicated in β-amyloid aggregation, the major pathology associated with Alzheimer disease. Presenilin mediates the proteolytic cleavage of the β-amyloid precursor protein to release β-amyloid, and mutations in presenilin can cause familial Alzheimer disease. We tested whether presenilin expression affects copper and zinc transport. Studying murine embryonic fibroblasts (MEFs) from presenilin knock-out mice or RNA interference of presenilin expression in HEK293T cells, we observed a marked decrease in saturable uptake of radiolabeled copper and zinc. Measurement of basal metal levels in 6-month-old presenilin 1 heterozygous knock-out (PS1+/−) mice revealed significant deficiencies of copper and zinc in several tissues, including brain. Copper/zinc superoxide dismutase (SOD1) activity was significantly decreased in both presenilin knock-out MEFs and brain tissue of presenilin 1 heterozygous knock-out mice. In the MEFs and PS1+/− brains, copper chaperone of SOD1 (CCS) levels were decreased. Zinc-dependent alkaline phosphatase activity was not decreased in the PS null MEFs. These data indicate that presenilins are important for cellular copper and zinc turnover, influencing SOD1 activity, and having the potential to indirectly impact β-amyloid aggregation through metal ion clearance