Age-dependent defects of alpha-synuclein oligomer uptake in microglia and monocytes

被引：148

作者：

Bliederhaeuser, Corinna ^{[1
]}

Grozdanov, Veselin ^{[1
]}

Speidel, Anna ^{[2
]}

Zondler, Lisa ^{[1
]}

Ruf, Wolfgang P. ^{[1
]}

Bayer, Hanna ^{[1
]}

Kiechle, Martin ^{[1
]}

Feiler, Marisa S. ^{[1
]}

Freischmidt, Axel ^{[1
]}

Brenner, David ^{[1
]}

Witting, Anke ^{[1
]}

Hengerer, Bastian ^{[2
]}

Faendrich, Marcus ^{[3
]}

Ludolph, Albert C. ^{[1
]}

Weishaupt, Jochen H. ^{[1
]}

Gillardon, Frank ^{[2
]}

Danzer, Karin M. ^{[1
]}

机构：

[1] Univ Ulm, Dept Neurol, Albert Einstein Allee 11, D-89081 Ulm, Germany

[2] Boehringer Ingelheim Pharma GmbH & Co KG, CNS Dis Res, Biberach, Germany

[3] Univ Ulm, Ctr Biomed Res, Inst Pharmaceut Biotechnol, D-89081 Ulm, Germany

来源：

ACTA NEUROPATHOLOGICA | 2016年 / 131卷 / 03期

关键词：

Microglia; Monocytes; Alpha-synuclein; Parkinson's disease; Exosomes; Aging; PARKINSONS-DISEASE; ALZHEIMERS-DISEASE; LEWY BODIES; CELLS; BRAIN; INFLAMMATION; CLEARANCE; EXOSOMES; NEURONS; MICE;

D O I：

10.1007/s00401-015-1504-2

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

Extracellular alpha-synuclein (alpha syn) oligomers, associated to exosomes or free, play an important role in the pathogenesis of Parkinson's disease (PD). Increasing evidence suggests that these extracellular moieties activate microglia leading to enhanced neuronal damage. Despite extensive efforts on studying neuroinflammation in PD, little is known about the impact of age on microglial activation and phagocytosis, especially of extracellular alpha syn oligomers. Here, we show that microglia isolated from adult mice, in contrast to microglia from young mice, display phagocytosis deficits of free and exosome-associated alpha syn oligomers combined with enhanced TNF alpha secretion. In addition, we describe a dysregulation of monocyte subpopulations with age in mice and humans. Accordingly, human monocytes from elderly donors also show reduced phagocytic activity of extracellular alpha syn. These findings suggest that these age-related alterations may contribute to an increased susceptibility to pathogens or abnormally folded proteins with age in neurodegenerative diseases.

引用

页码：379 / 391

页数：13

共 68 条

[1] Lysosomal dysfunction increases exosome-mediated alpha-synuclein release and transmission [J].

Alvarez-Erviti, Lydia ;

Seow, Yiqi ;

Schapira, Anthony H. ;

Gardiner, Chris ;

Sargent, Ian L. ;

Wood, Matthew J. A. ;

Cooper, J. Mark .

NEUROBIOLOGY OF DISEASE, 2011, 42 (03) :360-367

[2] Exosomes: vehicles for the transfer of toxic proteins associated with neurodegenerative diseases? [J].

Bellingham, Shayne A. ;

Guo, Belinda B. ;

Coleman, Bradley M. ;

Hill, Andrew F. .

FRONTIERS IN PHYSIOLOGY, 2012, 3

[3] Identification of a unique TGF-β dependent molecular and functional signature in microglia [J].

Butovsky, Oleg ;

Jedrychowski, Mark P. ;

Moore, Craig S. ;

Cialic, Ron ;

Lanser, Amanda J. ;

Gabriely, Galina ;

Koeglsperger, Thomas ;

Dake, Ben ;

Wu, Pauline M. ;

Doykan, Camille E. ;

Fanek, Zain ;

Liu, LiPing ;

Chen, Zhuoxun ;

Rothstein, Jeffrey D. ;

Ransohoffl, Richard M. ;

Gygi, Steven P. ;

Antel, Jack P. ;

Weiner, Howard L. .

NATURE NEUROSCIENCE, 2014, 17 (01) :131-143

[4] Sterile inflammation: sensing and reacting to damage [J].

Chen, Grace Y. ;

Nunez, Gabriel .

NATURE REVIEWS IMMUNOLOGY, 2010, 10 (12) :826-837

[5] Size and shape characterization of hydrated and desiccated exosomes [J].

Chernyshev, Vasiliy S. ;

Rachamadugu, Rakesh ;

Tseng, Yen Hsun ;

Belnap, David M. ;

Jia, Yunlu ;

Branch, Kyle J. ;

Butterfield, Anthony E. ;

Pease, Leonard F., III ;

Bernard, Philip S. ;

Skliar, Mikhail .

ANALYTICAL AND BIOANALYTICAL CHEMISTRY, 2015, 407 (12) :3285-3301

[6] Human CD14dim Monocytes Patrol and Sense Nucleic Acids and Viruses via TLR7 and TLR8 Receptors [J].

Cros, Jerome ;

Cagnard, Nicolas ;

Woollard, Kevin ;

Patey, Natacha ;

Zhang, Shen-Ying ;

Senechal, Brigitte ;

Puel, Anne ;

Biswas, Subhra K. ;

Moshous, Despina ;

Picard, Capucine ;

Jais, Jean-Philippe ;

D'Cruz, David ;

Casanova, Jean-Laurent ;

Trouillet, Celine ;

Geissmann, Frederic .

IMMUNITY, 2010, 33 (03) :375-386

[7] Different species of α-synuclein oligomers induce calcium influx and seeding [J].

Danzer, Karin M. ;

Haasen, Dorothea ;

Karow, Anne R. ;

Moussaud, Simon ;

Habeck, Matthias ;

Giese, Armin ;

Kretzschmar, Hans ;

Hengerer, Bastian ;

Kostka, Marcus .

JOURNAL OF NEUROSCIENCE, 2007, 27 (34) :9220-9232

[8] Exosomal cell-to-cell transmission of alpha synuclein oligomers [J].

Danzer, Karin M. ;

Kranich, Lisa R. ;

Ruf, Wolfgang P. ;

Cagsal-Getkin, Ozge ;

Winslow, Ashley R. ;

Zhu, Liya ;

Vanderburg, Charles R. ;

McLean, Pamela J. .

MOLECULAR NEURODEGENERATION, 2012, 7

[9] Heat-shock protein 70 modulates toxic extracellular α-synuclein oligomers and rescues trans-synaptic toxicity [J].

Danzer, Karin M. ;

Ruf, Wolfgang P. ;

Putcha, Preeti ;

Joyner, Daniel ;

Hashimoto, Tadafumi ;

Glabe, Charles ;

Hyman, Bradley T. ;

McLean, Pamela J. .

FASEB JOURNAL, 2011, 25 (01) :326-336

[10] IDENTIFICATION OF NORMAL AND PATHOLOGICAL AGING IN PROSPECTIVELY STUDIED NONDEMENTED ELDERLY HUMANS [J].

DICKSON, DW ;

CRYSTAL, HA ;

MATTIACE, LA ;

MASUR, DM ;

BLAU, AD ;

DAVIES, P ;

YEN, SH ;

ARONSON, MK .

NEUROBIOLOGY OF AGING, 1992, 13 (01) :179-189

← 1 2 3 4 5 6 7 →