Resting State Functional Connectivity in Preclinical Alzheimer’s Disease

There are over 120 types of brain tumor and approximately 45% of primary brain tumors are gliomas, of which glioblastoma multiforme (GBM) is the most common and aggressive with a median survival rate of 14 months. Despite progress in our knowledge, current therapies are unable to effectively combat primary brain tumors and patient survival remains poor. Tumor metabolism is important to consider in therapeutic approaches and is the focus of numerous research investigations. Lactate dehydrogenase A (LDHA) is a cytosolic enzyme, predominantly involved in anaerobic and aerobic glycolysis (the Warburg effect); however, it has multiple additional functions in non-neoplastic and neoplastic tissues, which are not commonly known or discussed. This review summarizes what is currently known about the function of LDHA and identifies areas that would benefit from further exploration. The current knowledge of the role of LDHA in the brain and its potential as a therapeutic target for brain tumors will also be highlighted. The Warburg effect appears to be universal in tumors, including primary brain tumors, and LDHA (because of its involvement with this process) has been identified as a potential therapeutic target. Currently, there are, however, no suitable LDHA inhibitors available for tumor therapies in the clinic.

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The Regulation and Function of Lactate Dehydrogenase A: Therapeutic Potential in Brain Tumor

Recent developments in the area of biological detection by optical sensing of molecular oxygen (O2) are reviewed, with particular emphasis on the quenched-phosphorescence O2 sensing technique. Following a brief introduction to the main principles, materials and formats of sensor technology, the main groups of applications targeted to biological detection using an O2 transducer are described. These groups include: enzymatic assays; analysis of respiration of mammalian and microbial cells, small organisms and plants; food and microbial safety; monitoring of oxygenation in cell cultures, 3D models of live tissue, bioreactors and fluidic chips; ex vivo and in vivo O2 measurements; trace O2 analysis. For these systems, which enable a range of new bioanalytical tasks with different samples and models in a minimally invasive, contact-less manner, with high sensitivity, flexibility and imaging capabilities in 2D and 3D, relevant practical examples are presented and their merits and limitations discussed. An outlook of future scientific and technological developments in the field is also provided.

Biological detection by optical oxygen sensing

https://pure.rug.nl/ws/files/66477432/1_s2.0_S156816371830093X_main.pdf

Towards frailty biomarkers: Candidates from genes and pathways regulated in aging and age-related diseases

The M1 and M2 polarized phenotypes dictate distinctive roles for macrophages as they participate in inflammatory disorders. There has been growing interest in the role of cellular metabolism in macrophage polarization. However, it is currently unclear whether different aspects of a specific metabolic program coordinately regulate this cellular process. In this study, we found that pyruvate dehydrogenase kinase 1 (PDK1), a key regulatory enzyme in glucose metabolism, plays an important role in the differential activation of macrophages. Knockdown of PDK1 diminished M1, whereas it enhanced M2 activation of macrophages. Mechanistically, PDK1 knockdown led to diminished aerobic glycolysis in M1 macrophages, which likely accounts for the attenuated inflammatory response in these cells. Furthermore, we found that mitochondrial respiration is enhanced during and required by the early activation of M2 macrophages. Suppression of glucose oxidation, but not that of fatty acids, inhibits this process. Consistent with its inhibitory role in early M2 activation, knockdown of PDK1 enhanced mitochondrial respiration in macrophages. Our data suggest that two arms of the glucose metabolism synergistically regulate the differential activation of macrophages. Our findings also highlight the central role of PDK1 in this event via controlling glycolysis and glucose oxidation.

/pdf/pyruvate-dehydrogenase-kinase-1-participates-in-macrophage-29gicoiit0.pdf

Pyruvate Dehydrogenase Kinase 1 Participates in Macrophage Polarization via Regulating Glucose Metabolism

Overexpression of Pyruvate Dehydrogenase Kinase 1 and Lactate Dehydrogenase A in Nerve Cells Confers Resistance to Amyloid β and Other Toxins by Decreasing Mitochondrial Respiration and Reactive Oxygen Species Production

Background: Neuroinflammation in the course of Alzheimer’s disease (AD) serves to exacerbate AD and promote disease progression. Amyloid Beta (AB) peptides and plaques are highly cytotoxic and trigger chronic inflammation in the cellular environment, contributing to the infiltration of macrophages within the brain. Upon activation, macrophages release pro-inflammatory cytokines that promote further neurotoxicity and apoptosis associated with AD. A major impediment to investigating neuroinflammation involving macrophage activity is the inability to discriminate between CNS-resident microglia-derived macrophages (mM) and hematogenous monocyte-derived macrophages (hM) in a temporal and spatial manner as these two populations of macrophages are morphologically and phenotypically similar in the activated state. Therefore, the overall goal of this research is to distinguish between hM and mM, and determine their respective roles in chronic inflammation associated with AD progression. Methods:The lys-EGFP-ki transgenic mouse line that enables the discrimination between mM and hMwas crossed with 5xFADmice. The resultant LysFADmice exhibited aggressive AD pathology of 5xFAD mice while enabling the spatial and temporal discrimination of mM and hM in the brain. Plaque load in the brains of these mice was measured using ELISA for AB42 in the cortex and hippocampus and spatial learning and memory was assessed using theMorrisWaterMaze.Results: Levels of AB42 were significantly higher in the brains of male and female LysFAD + compared to LysFAD littermates at 1.5 and 3 months, with AB levels peaking at 5 months and reaching a plateau by 7 months of age. Additionally, LysFAD+ male and female mice demonstrated spatial learning and memory deficits as measured by the Morris Water Maze test, at 5 and 7 months of age with deficits more pronounced in females. Conclusions: Based on these results, the time of onset of the behavioral deficits and accumulation of AB42 in the brains of LysFAD+ mice was identified to be 5-7 months. Therefore, immunostaining with specific antibodies for GFP, Iba1 (marker of microglia/macrophages) and AB plaques will be performed on frozen brain sections of these 5-7 month old mice in order to determine whether the macrophages surrounding AB plaques are hematogenous in origin or microglia-derived.

Shawn Albers

Papers

Overexpression of Pyruvate Dehydrogenase Kinase 1 and Lactate Dehydrogenase A in Nerve Cells Confers Resistance to Amyloid β and Other Toxins by Decreasing Mitochondrial Respiration and Reactive Oxygen Species Production

The role of neuroinflammation in alzheimer's disease