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Monday, February 2, 2015

Inflammation in the Brain:

Inflammation
Brain inflammation. Credit.
There are many ways by which brain tissue can get damaged, as is illustrated by the vast amount of different diseases there are. When neurons, the cells of the brain, get damaged it is frequently accompanied by inflammation. Cells send out distress calls which attract immune cells, tasked with clearing the debris and removing any cells that died from whatever it is that damaged the brain. However necessary, the immune system can overreact and thereby further increase damage, which is why clinicians often have to treat with anti-inflammatory drugs. The nano device developed by Wayne State University and the National Institute of Child Health and Human Development does something similar.
 How Astrocytes shift from being Neuro- Trophic to being Neuro-Toxic under Inflammatory pressure from Microglia
Although microglia are generally considered the resident immune cells in the brain, the impact of astrocytes on inflammation cannot be understated.
First, astrocytes outnumber microglia in the brain; second, astrocytes detect and amplify inflammatory signals from microglia, especially by self-propagation of the cytokine cycle to generate large amount of cytokines within a short period of time, and last but not least, astrocytes are in close proximity to neurons and synapses, so they directly affect neuronal functions.
Astrocytes rely primarily on ATP derived from glycolysis and the final product, pyruvate, is reduced to lactate, which supports energy demands in neurons when released from astrocytes
In turn, astrocyte-derived lactate is oxidized to pyruvate in neurons, a substrate for the pyruvate dehydrogenase complex that furnishes acetyl-CoA to the tricarboxylic acid; the energy-carrying molecules in this case are the electron-rich NADH and FADH2.
Astrocytes amplify inflammatory signals rather than standing in the first line of defense as microglia; therefore, their sustained production of inflammatory mediators require a steady supply of ATP, which could be supported by oxidative metabolism rather than glycolysis.
Inflammatory reactions in astrocytes in response to infection or other stressors are metabolically expensive events (and may stimulate mitochondrial metabolism for the energy support.
Enhanced mitochondrial respiration in astrocytes limits the substrate supply from astrocytes to neurons; this may be viewed as an adaptive mechanism to altered cellular inflammatory-redox environment with age. These metabolic changes were associated with an age-dependent increase in hydrogen peroxide generation (largely ascribed to an enhanced expression of NOX2) and NFκB signaling in the cytosol as well as its translocation to the nucleus.
Astrocytes also displayed augmented responses with age to inflammatory cytokines, IL-1β, and TNFα. Activation of NFκB signaling resulted in increased expression of nitric oxide synthase 2 (inducible nitric oxide synthase), leading to elevated nitric oxide production.
Astrocytes are generally considered neurotrophic inasmuch as providing neurons with energy substrates and recycling neurotransmitters. However, data in this study showed that astrocytes reduced their neurotrophic functions by utilizing energy substrates for their own metabolism rather than transferring them to neurons.
Hence, the high energy demands imposed by neuronal function are not supported by the age-declining neurotrophic function of astrocytes; challenges to this neurotrophic support – in terms of astrocyte-generated lactate – become exacerbated with the age-dependent reduction in expression and translocation to the plasma membrane of neuronal glucose transporters (GLUT3 and GLUT4)
An increase in reactive astrocytes is a hallmark of brain aging and neurodegenerative diseases. It may be surmised that increased mitochondrial aerobic metabolism and inflammatory responses support the functionality switch of astrocytes, from neurotrophic to neurotoxic with age.
Specifically, upon stimulation by IL-1b, young astrocytes showed moderate activation of cytosolic NFjB signaling (assessed by decreased IjBa/NFjB ratio), whereas astrocytes from old rats exhibited a much stronger response to IL-1b In support of this, upon IL-1b stimulation, older astrocytes had a larger increase in nuclear translocation of NFjB than young astrocytes.
IL-1β and TNFα treatment stimulated mitochondrial oxidative metabolism and mitochondrial biogenesis in astrocytes.
It may be surmised that increased mitochondrial aerobic metabolism and inflammatory responses are interconnected and support the functionality switch of astrocytes, from neurotrophic to neurotoxic with age.
Aging is usually accompanied by recurrent injury, invasion, and other insults causing chronic inflammation.
Strategies that modulate substrate metabolism in astrocytes would be innovative approaches to address impaired neuronal function and neurodegener- ation with age.