Locus ceruleus controls Alzheimer's disease pathology by modulating microglial functions through norepinephrine

被引：375

作者：

Heneka, Michael T. ^{[1
,2
]}

Nadrigny, Fabian ^{[3
]}

Regen, Tommy ^{[4
]}

Martinez-Hernandez, Ana ^{[5
]}

Dumitrescu-Ozimek, Lucia ^{[1
,2
]}

Terwel, Dick ^{[1
,2
]}

Jardanhazi-Kurutz, Daniel ^{[6
]}

Walter, Jochen ^{[1
,2
]}

Kirchhoff, Frank ^{[3
,7
]}

Hanisch, Uwe-Karsten ^{[4
]}

Kummer, Markus P. ^{[1
,2
]}

机构：

[1] Univ Bonn, Deutsch Zentrum Neurodegenerat Erkrankunge, D-53105 Bonn, Germany

[2] Univ Bonn, Dept Neurol, D-53105 Bonn, Germany

[3] Max Planck Inst Expt Med, D-37075 Gottingen, Germany

[4] Univ Gottingen, Inst Neuropathol, D-37075 Gottingen, Germany

[5] Max Planck Inst Biophys Chem, D-37077 Gottingen, Germany

[6] Bayer Schering Pharma, D-13353 Berlin, Germany

[7] Univ Saarland, Inst Physiol, D-66421 Homburg, Germany

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2010年 / 107卷 / 13期

关键词：

neuroinflammation; amyloid beta; neurodegeneration; phagocytosis; DOPAMINE-BETA-HYDROXYLASE; TRANSGENIC MICE; SENILE DEMENTIA; BRAIN; NEURONS; NORADRENALINE; COERULEUS; PROTEIN; CELLS; DEGENERATION;

D O I：

10.1073/pnas.0909586107

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Locus ceruleus (LC)-supplied norepinephrine (NE) suppresses neuroinflammation in the brain. To elucidate the effect of LC degeneration and subsequent NE deficiency on Alzheimer's disease pathology, we evaluated NE effects on microglial key functions. NE stimulation of mouse microglia suppressed A beta-induced cytokine and chemokine production and increased microglial migration and phagocytosis of A beta. Induced degeneration of the locus ceruleus increased expression of inflammatory mediators in APP-transgenic mice and resulted in elevated A beta deposition. In vivo laser microscopy confirmed a reduced recruitment of microglia to A beta plaque sites and impaired microglial A beta phagocytosis in NE-depleted APP-transgenic mice. Supplying the mice the norepinephrine precursor L-threo-DOPS restored microglial functions in NE-depleted mice. This indicates that decrease of NE in locus ceruleus projection areas facilitates the inflammatory reaction of microglial cells in AD and impairs microglial migration and phagocytosis, thereby contributing to reduced A beta clearance. Consequently, therapies targeting microglial phagocytosis should be tested under NE depletion.

引用

页码：6058 / 6063

页数：6

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