Angiotensin Type 1 Receptor Antagonists Protect Against Alpha-Synuclein-Induced Neuroinflammation and Dopaminergic Neuron Death
Rodriguez-Perez, Ana I. (Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas)
Sucunza, Diego (University of Navarra. Neurosciences Division, Centro de Investigación Médica Aplicada)
Pedrosa, Maria A. (Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas)
Garrido-Gil, Pablo (Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas)
Kulisevsky, Jaime (Institut d'Investigació Biomèdica Sant Pau)
Lanciego, Jose L. (University of Navarra. Neurosciences Division, Centro de Investigación Médica Aplicada)
Labandeira-Garcia, Jose L. (Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas)
Universitat Autònoma de Barcelona

Fecha:	2018
Resumen:	The loss of dopaminergic neurons and α-synuclein accumulation are major hallmarks of Parkinson's disease (PD), and it has been suggested that a major mechanism of α-synuclein toxicity is microglial activation. The lack of animal models that properly reproduce PD, and particularly the underlying synucleinopathy, has hampered the clarification of PD mechanisms and the development of effective therapies. Here, we used neurospecific adeno-associated viral vectors serotype 9 coding for either the wild-type or mutated forms of human alpha-synuclein (WT and SynA53T, respectively) under the control of a synapsin promoter to further induce a marked dopaminergic neuron loss together with an important microglial neuroinflammatory response. Overexpression of neuronal alpha-synuclein led to increased expression of angiotensin type 1 receptors and NADPH oxidase activity, together with a marked increase in the number of OX-6-positive microglial cells and expression of markers of phagocytic activity (CD68) and classical pro-inflammatory/M1 microglial phenotype markers such as inducible nitric oxide synthase, tumor necrosis factor alpha, interleukin-1β, and IL-6. Moreover, a significant decrease in the expression of markers of immunoregulatory/M2 microglial phenotype such as the enzyme arginase-1 was constantly observed. Interestingly, alpha-synuclein-induced changes in microglial phenotype markers and dopaminergic neuron death were inhibited by simultaneous treatment with the angiotensin type 1 blockers candesartan or telmisartan. Our results suggest the repurposing of candesartan and telmisartan as a neuroprotective strategy for PD.
Ayudas:	Ministerio de Economía y Competitividad BFU2015-70523 Ministerio de Economía y Competitividad BFU2017-82407-R
Nota:	Altres ajuts: This study received funding from the Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas' intramural program (2014/01 and 2017/02), Galician Government (Xunta de Galicia, Consellería de Educación; GRC2014/002), Navarra Government (Departamento de Salud; 046-2017), and Fondo Europeo de Desarrollo Regional (Regional European Development Fund).
Nota:	Altres ajuts: MSCBS/PI17-00828
Nota:	Altres ajuts: MSCBS/RD16-0011-0016
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Candesartan ; Microglia ; Neurodegeneration ; Parkinson ; Telmisartan ; Viral vectors
Publicado en:	Neurotherapeutics, Vol. 15 (july 2018) , p. 1063-1081, ISSN 1878-7479

DOI: 10.1007/s13311-018-0646-z
PMID: 29987762

19 p, 13.2 MB

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