Energy metabolism and inflammation in brain aging and Alzheimer’s disease

Abstract

The high energy demand of the brain renders it sensitive to changes in energy fuel supply and mitochondrial function. Deficits in glucose availability and mitochondrial function are well-known hallmarks of brain aging and are particularly accentuated in neurodegenerative disorders such as Alzheimer’s disease. As important cellular sources of H2O2, mitochondrial dysfunction is usually associated with altered redox status. Bioenergetic deficits and chronic oxidative stress are both major contributors to cognitive decline associated with brain aging and Alzheimer’s disease. Neuroinflammatory changes, including microglial activation and production of inflammatory cytokines, are observed in neurodegenerative diseases and normal aging. The bioenergetic hypothesis advocates for sequential events from metabolic deficits to propagation of neuronal dysfunction, to aging, and to neurodegeneration, while the inflammatory hypothesis supports microglia activation as the driving force for neuroinflammation. Nevertheless, growing evidence suggests that these diverse mechanisms have redox dysregulation as a common denominator and connector. An independent view of the mechanisms underlying brain aging and neurodegeneration is being replaced by one that entails multiple mechanisms coordinating and interacting with each other. This review focuses on the alterations in energy metabolism and inflammatory responses and their connection via redox regulation in normal brain aging and Alzheimer’s disease. Interactions of these systems is reviewed based on basic research and clinical studies.

Direct and indirect pro-inflammatory cytokine response resulting from TC-83 infection of glial cells

“…The contribution of mitochondrial events to neuroinflammation has been extensively studied in the context of neurodegenerative diseases, and has recently been explored in the context of viral infections [13–23]. In these instances, alterations to mitochondrial homeostasis abrogate its function resulting in altered cellular redox status, accumulation of reactive oxygen species (ROS), dysregulated energy metabolism, mitophagy, increased neuroinflammation, collapsed mitochondrial networks, and axonal demyelination.…”

Neuroprotection in Perimenopausal Women

“…Genetic analyses demonstrated that the menstrual cycles acyclicity is accompanied by a rise in genes required for fatty acid metabolism, a decline of genes required for mitochondrial function, β-amyloid degradation, and neuroinflammation including increased number in microglia population in aging hippocampus [41], plus the shift of microglia activation with predominant production of inflammatory cytokines [42], and a higher basal level of complement cascade genes and interleukin 1 receptor-like 1 in women versus men [43].…”

“…According to these, one may consider a metabolic inflammatory axis during brain aging and in neurodegenerative diseases [42]. In conditions of hypoglycemia, lactate can serve as an auxiliary fuel by metabolism of glycogen stores to generate glucose and subsequently lactate; some studies revealed that glial cells are likely to produce lactate in excess to its utilization by neurons [46].…”

Introduction to Special Issue on Mitochondrial Redox Signaling in Health and Disease

“…H2O2-mediated redox regulation of signaling and transcription entails thiol/disulfide exchange reactions [14,15]. In this special issue, mitochondrion-derived H2O2: (a) establishes a link between energy metabolism and inflammatory responses [16], acting on redox-sensitive targets such as Nrf2, NFB, JNK, IIS [17,18], and stimulates mitochondrial biogenesis [19]; (b) is at the interface between bioenergetics, autophagy, and circadian control [20]; (c) is controlled during cholesterol oxidation in steroidogenic cells and brings together the coordinated activities of peroxiredoxin III -the major H2O2 reducing system within mitochondria-sulfiredoxin, which recovers hyperoxidized peroxiredoxin III [21]; (d) is involved in the activation of phospholipases and is an important physiological function associated with O2 sensing in astrocytes and regulation of breathing [22]; (e) regulates mitogenic cellular signaling in proliferating cells through HIF activation and transcriptional activation of genes required for metabolic adaptations to proliferation and induction of angiogenesis [23]. It has been proposed that transducing an H2O2 signal can be accomplished by peroxiredoxin-2 and STAT3 [24].…”