Upregulation of Glycolytic Enzymes, Mitochondrial Dysfunction and Increased Cytotoxicity in Glial Cells Treated with Alzheimer’s Disease Plasma

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder associated with increased oxidative stress and neuroinflammation. Markers of increased protein, lipid and nucleic acid oxidation and reduced activities of antioxidant enzymes have been reported in AD plasma. Amyloid plaques in the AD brain elicit a range of reactive inflammatory responses including complement activation and acute phase reactions, which may also be reflected in plasma. Previous studies have shown that human AD plasma may be cytotoxic to cultured cells. We investigated the effect of pooled plasma (n = 20 each) from healthy controls, individuals with amnestic mild cognitive impairment (aMCI) and Alzheimer’s disease (AD) on cultured microglial cells. AD plasma and was found to significantly decrease cell viability and increase glycolytic flux in microglia compared to plasma from healthy controls. This effect was prevented by the heat inactivation of complement. Proteomic methods and isobaric tags (iTRAQ) found the expression level of complement and other acute phase proteins to be altered in MCI and AD plasma and an upregulation of key enzymes involved in the glycolysis pathway in cells exposed to AD plasma. Altered expression levels of acute phase reactants in AD plasma may alter the energy metabolism of glia.

N‐Acetylgalactosamine‐Targeted Delivery of Dendrimer‐Doxorubicin Conjugates Influences Doxorubicin Cytotoxicity and Metabolic Profile in Hepatic Cancer Cells

“…Valbuena et al verified the increase in glycolysis and TCA cycle was a result of poor adaptation to ROS generated in amyotrophic lateral sclerosis neuronal cells, and was a sign of neuronal death . Further, plasma from patients with Alzheimer's disease, a neurodegenerative disorder associated with increased oxidative stress, caused mitochondrial dysfunction and increased glycolysis as a compensatory action, ultimately leading to a loss of cell viability, as studied by Jayasena et al Therefore, our data may suggest that the delivery of TCM F1 and D1 moieties causes high oxidative stress leading to upregulation of glycolysis and the TCA cycle and may be the primary mechanism of toxicity observed with P1 and P2 conjugates. This also explains the three‐ to fivefold increase in oxidized glutathione (glutathione disulfide; GSSG) present in P1/P2‐treated cells (Figure , Panel B), which is normally upregulated to scavenge ROS .…”

“…We hypothesize that the increase in glycolysis is a response to oxidative stress caused by the generation of ROS, a primary mechanism of DOX and DOX‐metabolite toxicity . This is supported by several studies correlating increased glycolysis with oxidative stress and mitochondrial dysfunction . Wu and Wei in their work showed increased glycolytic flux was a result of oxidative stress in skin fibroblasts from patients with myoclonic epilepsy and ragged‐red fiber syndrome, in an attempt to generate NADH to help mitigate ROS generation .…”

Microglia-Specific Metabolic Changes in Neurodegeneration

“…Previous studies have shown that Aβ-plaques in the AD brain elicit inflammatory responses, which may also be reflected systemically in plasma. Treatment with AD plasma was found to affect cellular bioenergetics in a microglial cell line by upregulating glycolytic flux and enzyme expression arguably to compensate for mitochondrial dysfunction and decreased cell viability [107]. This observation supports the increasing body of evidence that inflammation and energy metabolism are closely linked phenomena in which microglial energetics may also have a significant contribution.…”

Age- and Brain Region-Specific Changes of Glucose Metabolic Disorder, Learning, and Memory Dysfunction in Early Alzheimer’s Disease Assessed in APP/PS1 Transgenic Mice Using 18F-FDG-PET

“…When existing neurons cannot take over lost ones, glucose metabolism begins to decline. Moreover, innate immune-mediated neuroinflammation also occurs in company with Aβ accumulation in AD, which often leads to abundant inflammatory cells, including glial activation that expresses high levels of glucose transporters and thus increases brain glycolytic activity [23,24,25]. Our study revealed the entorhinal cortex and hippocampus as regions affected first with glucose disorders, perhaps because these regions are highly dependent on the insulin signaling pathway and are initially subject to Aβ accumulation [26,27].…”