b1-integrin-dependent migration of microglia response to neuron-released a-synuclein

다국어 초록 (Multilingual Abstract)

Chronic neuroinflammation is an integral pathological feature of major neurodegenerative diseases. The recruitment of microglia to affected brain regions and the activation of these cells are the major events leading to disease-associated neuroinflammation.In a previous study, we showed that neuron-released a-synuclein can activate microglia through activating the Toll-like receptor 2 (TLR2) pathway, resulting in proinflammatory responses. However, it is not clear whether other signaling pathways are involved in the migration and activation of microglia in response to neuron-released a-synuclein. In the current study, wedemonstrated that TLR2 activation is not sufficient for all of the changes manifested by microglia in response to neuronreleased a-synuclein. Specifically, the migration of and morphological changes in microglia, triggered by neuron-released a-synuclein, did not require the activation of TLR2, whereas increased proliferation and production of cytokines were strictly under the control of TLR2. Construction of a hypothetical signaling network using computational tools and experimental validation with various peptide inhibitors showed that b1-integrin was necessary for both the morphological changes and the migration. However, neither proliferation nor cytokine production by microglia was dependent on the activation of b1-integrin.
These results suggest that b1-integrin signaling is specifically responsible for the recruitment of microglia to the diseaseaffected brain regions, where neurons most likely release relatively high levels of a-synuclein.

참고문헌 (Reference)

1 Barkan D, "beta1-integrin : a potential therapeutic target in the battle against cancer recurrence" 17 : 7219-7223, 2011

2 Spillantini MG, "alpha-Synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with lewy bodies" 95 : 6469-6473, 1998

3 Fellner L, "Toll-like receptor 4 is required for alpha-synuclein dependent activation of microglia and astroglia" 61 : 349-360, 2013

4 Lashuel HA, "The many faces of alphasynuclein : from structure and toxicity to therapeutic target" 14 : 38-48, 2013

5 Takada Y, "The integrins" 8 : 215-, 2007

6 Long-Smith CM, "The influence of microglia on the pathogenesis of Parkinson’s disease" 89 : 277-287, 2009

7 Matter ML, "The alpha5beta1 integrin mediates elimination of amyloid-beta peptide and protects against apoptosis" 141 : 1019-1030, 1998

8 Su X, "Synuclein activates microglia in a model of Parkinson’s disease" 29 : 1690-1701, 2008

9 Mollenhauer B, "Quantification of alpha-synuclein in cerebrospinal fluid as a biomarker candidate: review of the literature and considerations for future studies" 4 : 683-699, 2010

10 Jeon H, "Plasminogen activator inhibitor type 1 regulates microglial motility and phagocytic activity" 9 : 149-, 2012

11 Kettenmann H, "Physiology of microglia" 91 : 461-553, 2011

12 Wright S, "Perlecan domain V inhibits alpha2 integrin-mediated amyloid-beta neurotoxicity" 33 : 1379-1388, 2012

13 Dauer W, "Parkinson’s disease : mechanisms and models" 39 : 889-909, 2003

14 Jang A, "Non-classical exocytosis of alpha-synuclein is sensitive to folding states and promoted under stress conditions" 113 : 1263-1274, 2010

15 Forno LS, "Neuropathology of Parkinson’s disease" 55 : 259-272, 1996

16 Kim C, "Neuron-released oligomeric alpha-synuclein is an endogenous agonist of TLR2 for paracrine activation of microglia" 1562-, 2013

17 Hirsch EC, "Neuroinflammation in Parkinson’s disease: a target for neuroprotection?" 8 : 382-397, 2009

18 Koenigsknecht J, "Microglial phagocytosis of fibrillar betaamyloid through a beta1 integrin-dependent mechanism" 24 : 9838-9846, 2004

19 Zhang W, "Microglial PHOX and Mac-1 are essential to the enhanced dopaminergic neurodegeneration elicited by A30P and A53T mutant alpha-synuclein" 55 : 1178-1188, 2007

20 Zhang D, "Microglial MAC1 receptor and PI3K are essential in mediating beta-amyloid peptide-induced microglial activation and subsequent neurotoxicity" 8 : 3-, 2011

21 Hanisch UK, "Microglia: active sensor and versatile effector cells in the normal and pathologic brain" 10 : 1387-1394, 2007

22 Perry VH, "Microglia in neurodegenerative disease" 6 : 193-201, 2010

23 Carson MJ, "Microglia as liaisons between the immune and central nervous systems : functional implications for multiple sclerosis" 40 : 218-231, 2002

24 Wake H, "Microglia : actively surveying and shaping neuronal circuit structure and function" 36 : 209-217, 2013

25 Bae EJ, "Lipid peroxidation product 4-hydroxy-2-nonenal promotes seeding-capable oligomer formation and cell-to-cell transfer of alpha-synuclein" 18 : 770-783, 2013

26 Ogata H, "KEGG : Kyoto encyclopedia of genes and genomes" 27 : 29-34, 1999

27 Bozzo C, "Involvement of beta(1)integrin in betaAP-induced apoptosis in human neuroblastoma cells" 25 : 1-8, 2004

28 Lee HJ, "Intravesicular localization and exocytosis of alpha-synuclein and its aggregates" 25 : 6016-6024, 2005

29 Jeon YJ, "Interaction of microglia and amyloid-beta through beta2-integrin is regulated by RhoA" 19 : 1661-1665, 2008

30 Sabo S, "Interaction of beta-amyloid peptides with integrins in a human nerve cell line" 184 : 25-28, 1995

31 Frasca G, "Integrins mediate beta-amyloid-induced cell-cycle activation and neuronal death" 86 : 350-355, 2008

32 Huttenlocher A, "Integrins in cell migration" 3 : a005074-, 2011

33 Goodwin JL, "Integrin Mac-1 and betaamyloid in microglial release of nitric oxide" 768 : 279-286, 1997

34 Desplats P, "Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein" 106 : 13010-13015, 2009

35 Danzer KM, "Heat-shock protein 70 modulates toxic extracellular alpha-synuclein oligomers and rescues trans-synaptic toxicity" 25 : 326-336, 2011

36 Yuskaitis CJ, "Glycogen synthase kinase-3 regulates microglial migration, inflammation, and inflammation-induced neurotoxicity" 21 : 264-273, 2009

37 이혜진, "Dopamine promotes formation and secretion of non-fibrillar alpha-synuclein oligomers" 생화학분자생물학회 43 (43): 216-222, 2011

38 Lee HJ, "Direct transfer of alpha-synuclein from neuron to astroglia causes inflammatory responses in synucleinopathies" 285 : 9262-9272, 2010

39 Takeuchi O, "Differential roles of TLR2 and TLR4 in recognition of gram-negative and gram-positive bacterial cell wall components" 11 : 443-451, 1999

40 Shannon P, "Cytoscape : a software environment for integrated models of biomolecular interaction networks" 13 : 2498-2504, 2003

41 Kim C, "Controlling the mass action of alpha-synuclein in Parkinson’s disease" 107 : 303-316, 2008

42 Mrak RE, "Common inflammatory mechanisms in Lewy body disease and Alzheimer disease" 66 : 683-686, 2007

43 Eikelenboom P, "Cellular and substrate adhesion molecules (integrins) and their ligands in cerebral amyloid plaques in Alzheimer’s disease" 424 : 421-427, 1994

44 Wu DC, "Blockade of microglial activation is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson disease" 22 : 1763-1771, 2002

45 이혜진, "Autophagic failure promotes the exocytosis and intercellular transfer of a-synuclein" 생화학분자생물학회 45 (45): 1-9, 2013

46 Emmanouilidou E, "Assessment of alpha-synuclein secretion in mouse and human brain parenchyma" 6 : e22225-, 2011

47 Chang J, "Antibodymediated inhibition of integrin alpha5beta1 blocks neurotoxic prion peptide PrP106-126-induced activation of BV2 microglia" 48 : 248-252, 2012

48 Wright S, "Alpha2beta1 and alphaVbeta1 integrin signaling pathways mediate amyloid-beta-induced neurotoxicity" 28 : 226-237, 2007

49 Liu Y, "A novel molecular mechanism for nitrated {alpha}-synuclein-induced cell death" 3 : 239-249, 2011

50 Bamberger ME, "A cell surface receptor complex for fibrillar beta-amyloid mediates microglial activation" 23 : 2665-2674, 2003

51 Ghiso J, "A 109-amino-acid C-terminal fragment of Alzheimer’s-disease amyloid precursor protein contains a sequence, -RHDS-, that promotes cell adhesion" 288 (288): 1053-1059, 1992