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Review
, 100, 108-122

Energy Metabolism and Inflammation in Brain Aging and Alzheimer's Disease

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Review

Energy Metabolism and Inflammation in Brain Aging and Alzheimer's Disease

Fei Yin et al. Free Radic Biol Med.

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. Interaction of these systems is reviewed based on basic research and clinical studies.

Keywords: Alzheimer’s disease; Brain aging; Glucose metabolism; Inflammation; Mitochondria; Redox control.

Figures

Fig. 1
Fig. 1. Insulin/IGF1 signaling (IIS) is primarily orchestrated through insulin and IGF1 and the PI3K/Akt and ERK1/2 signaling pathways
Binding of the ligand to insulin receptor or IGF1 receptor activates the insulin receptor substrate (IRS). Binding of PI3K to the phosphorylated IRS activates the PI3K/Akt signaling network, whereas recruitment of Grb2 to the IRS results in Sos-mediated activation of the Ras-MAPK pathway. The PI3K/Akt pathway effects changes in carbohydrate and lipid metabolism and modulates glucose uptake, whereas the Ras-MAPK pathway is involved in cell growth and differentiation and protein synthesis.
Fig. 2
Fig. 2. Glucose transporters (GLUTs) in the brain
GLUT1 (55kDa) is expressed in endothelial cells of the BBB; GLUT1 (45kDa)-mediated transport of glucose into astrocytes; glucose uptake into neurons via neuronal GLUTs, GLUT3 and the insulin-sensitive GLUT4.
Fig. 3
Fig. 3. Mitochondrial energy metabolism in brain
Pyruvate imported by the mitochondrial pyruvate carrier (MPC) is converted to acetyl-CoA, which enters the TCA cycle to generate NADH, the reducing equivalents of which flow through the respiratory chain and oxidative phosphorylation. ATP generated by oxidative phosphorylation together with glutamate and GABA are critical for synaptic plasticity in brain. Glutamate is primarily generated from (a) α-ketoglutarate by glutamate dehydrogenase and (b) astrocyte-originated glutamine by glutaminase. GABA is produced by glutamate decarboxylase from glutamate. Acetyl-CoA is also a co-substrate for the synthesis of N-acetylaspartate (NAA) by aspartate N-acetyltransferase (Asp-NAT). Aspartate generated from oxaloacetate (coupled to the conversion of glutamate to α-ketoglutarate) is critical in cell proliferation.
Fig. 4
Fig. 4. H2O2 modulates IIS in a concentration-dependent manner
Lower concentration of H2O2 activates IIS via (a) oxidation and activation of insulin receptor, (b) oxidation and inhibition of phosphatases that negative regulate IIS including PTP1B and PTEN, and (c) activation of Akt. Conversely, higher levels of H2O2 inactivate IIS due to the stimulation of inhibitory pathways of IIS such as JNK and IKK.
Fig. 5
Fig. 5. NFκB signaling in the inflammatory response
NFκB activation, and subsequent translocation to the nucleus can be initiated by different PAMPs or DAMPs via the toll-like receptors (e.g., TLR4). Mitochondrial H2O2 can facilitate NFκB activation by modulating the redox sensitive Syk and IKK pathways which phosphorylate the inhibitory protein IκB and lead to IκB ubiquitination and degradation, thereby releasing NFκB and its translocation to the nucleus.
Fig. 6
Fig. 6. Mitochondrion-driven activation of the NLRP3 inflammasome
H2O2 generated by mitochondria and NADPH oxidase (NOX) enzymes are major sources for NLRP3 priming and activation. NOX enzymes are dependent on mitochondrial H2O2 for their activation. Once primed, the inflammasome components oligomerize and form a complex with ACS, generating a platform for caspase-1 to catalyze the proteolytic activation of IL1β.
Fig. 7
Fig. 7. Coordination of metabolic, redox, and inflammatory signals in brain aging and neurodegeneration
The metabolic-, redox- and inflammatory components are interconnected and signals (metabolic signal: ATP; redox signal: H2O2 and NO; inflammatory signal: cytokines) originated from each component are involved in intra- (inner circle) and inter- (outer circle) cellular communications in the brain.

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