Neurodegenerative diseases: Microglia's little helper
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The locus coeruleus is the major source of noradrenaline in the brain, and its degeneration in Alzheimer’s disease is closely associated with the progression of symptoms. It has recently been shown that noradrenergic transmission can decrease amyloid-β (Aβ) deposition, but how it achieves this effect was unclear. Heneka et al. now show that noradrenaline acts by preventing neuroinflammation and stimulating microglial recruitment and phagocytosis of Aβ. The authors found that the Aβ-induced expression of pro- inflammatory genes in microglia was abolished in the presence of noradrenaline. Moreover, noradrena- line increased microglial migration and phagocytosis of fluorescence- labelled Aβ. These effects seemed to be mediated by activation of β-adrenoceptors, as treatment with the specific agonist isoproterenol yielded similar results. To test their observations in vivo, the authors treated mice that overexpressed amyloid precursor protein (APP) with DSP4, a neuro- toxin that specifically targets axons arising from the locus coeruleus. Treated mice exhibited a 70–80% reduction in forebrain noradrenaline levels and a concomitant increase in Aβ deposition in the hippocampus and the frontal cortex. The number of activated microglia surrounding the plaques and the amount of Aβ inclusions in microglial cells was reduced after treatment. This suggests that lack of noradrenergic innervation from the locus coeruleus impairs the recruitment of microglia to the plaques and subsequent phagocytosis of Aβ, thereby enhancing plaque formation. Finally, treatment with the noradrenaline precursor l-threo- dihydroxyphenylserine reversed the effects of noradrenaline depletion on microglial migration and phagocytosis in APP-transgenic mice. These findings emphasize the role of noradrenaline as a regulator of microglial function, in addition to its more well-known function in neurotransmission. Moreover, the data explain the association between locus coeruleus degeneration and Alzheimer’s disease progression, suggesting that noradrenergic inner- vation from this nucleus provides an important defence mechanism against chronic Aβ deposition. Cristian Bodo ORIGINAL RESEARCH PAPER Heneka, M. T. et al. Locus ceruleus controls Alzheimer’s disease pathology by modulating microglial functions through norepinephrine. Proc. Natl Acad. Sci. USA 107, 6058–6063 (2010) NEURODEGENERATIVE DISEASES Microglia’s little helper RESEARCH HIGHLIGHTS NATURE REVIEWS | NEUROSCIENCE VOLUME 11 | MAY 2010 Nature Reviews Neuroscience | AOP, published online 9 April 2010; doi:10.1038/nrn2843 © 20 Macmillan Publishers Limited. All rights reserved 10
Transcript of Neurodegenerative diseases: Microglia's little helper
The locus coeruleus is the major source of noradrenaline in the brain, and its degeneration in Alzheimer’s disease is closely associated with the progression of symptoms. It has recently been shown that noradrenergic transmission can decrease amyloid-β (Aβ) deposition, but how it achieves this effect was unclear. Heneka et al. now show that noradrenaline acts by preventing neuroinflammation and stimulating microglial recruitment and phagocytosis of Aβ.
The authors found that the Aβ-induced expression of pro-inflammatory genes in microglia was abolished in the presence of noradrenaline. Moreover, noradrena-line increased microglial migration and phagocytosis of fluorescence-labelled Aβ. These effects seemed to be mediated by activation of β-adrenoceptors, as treatment with the specific agonist isoproterenol yielded similar results.
To test their observations in vivo, the authors treated mice that overexpressed amyloid precursor protein (APP) with DSP4, a neuro-toxin that specifically targets axons arising from the locus coeruleus. Treated mice exhibited a 70–80% reduction in forebrain noradrenaline levels and a concomitant increase in
Aβ deposition in the hippocampus and the frontal cortex. The number of activated microglia surrounding the plaques and the amount of Aβ inclusions in microglial cells was reduced after treatment. This suggests that lack of noradrenergic innervation from the locus coeruleus impairs the recruitment of microglia to the plaques and subsequent phagocytosis of Aβ, thereby enhancing plaque formation. Finally, treatment with the noradrenaline precursor l-threo-dihydroxyphenylserine reversed the effects of noradrenaline depletion on microglial migration and phagocytosis in APP-transgenic mice.
These findings emphasize the role of noradrenaline as a regulator of microglial function, in addition to its more well-known function in neurotransmission. Moreover, the data explain the association between locus coeruleus degeneration and Alzheimer’s disease progression, suggesting that noradrenergic inner-vation from this nucleus provides an important defence mechanism against chronic Aβ deposition.
Cristian Bodo
ORIGINAL RESEARCH PAPER Heneka, M. T. et al. Locus ceruleus controls Alzheimer’s disease pathology by modulating microglial functions through norepinephrine. Proc. Natl Acad. Sci. USA 107, 6058–6063 (2010)
N E u R O d E G E N E R At I v E d I S E A S E S
Microglia’s little helper
R e s e a R c h h i g h l i g h t s
nATure revIewS | NeuroscieNce voluMe 11 | MAy 2010
Nature Reviews Neuroscience | AoP, published online 9 April 2010; doi:10.1038/nrn2843
© 20 Macmillan Publishers Limited. All rights reserved10
