Brain infusion of α-synuclein oligomers induces motor and non-motor Parkinson's disease-like symptoms in mice
| Autor: | Paula S. Frost, Julia R. Clarke, Fernanda S Neves, Carolina A. Braga, Cláudia P. Figueiredo, Juliana T.S. Fortuna, Fernanda G. De Felice, Debora Foguel, Rafaella Araujo Gonçalves, Flávia Carvalho Alcantara Gomes, Matthias Gralle, Luciana Romão, Luan Pereira Diniz, Sergio T. Ferreira, Danielle Beckman, Félix Alexandre Antunes Soares, Fernanda G. Q. Barros-Aragão, Luis E. Santos, Daniele Coradini Zamberlan |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Male medicine.medical_specialty Elevated plus maze Parkinson's disease Tyrosine 3-Monooxygenase Substantia nigra Mice Transgenic Behavioral Symptoms Open field 03 medical and health sciences Behavioral Neuroscience Mice Olfaction Disorders 0302 clinical medicine Discrimination Psychological Dopamine Mesencephalon Internal medicine medicine Animals Humans Maze Learning Cells Cultured Injections Intraventricular Neurons Tyrosine hydroxylase Dopaminergic Brain Parkinson Disease Recognition Psychology medicine.disease Embryo Mammalian Olfactory bulb Disease Models Animal 030104 developmental biology Endocrinology alpha-Synuclein Psychology Peptides Neuroscience 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Behavioural brain research. 333 |
| ISSN: | 1872-7549 |
| Popis: | Parkinson's disease (PD) is characterized by motor dysfunction, which is preceded by a number of non-motor symptoms including olfactory deficits. Aggregation of α-synuclein (α-syn) gives rise to Lewy bodies in dopaminergic neurons and is thought to play a central role in PD pathology. However, whether amyloid fibrils or soluble oligomers of α-syn are the main neurotoxic species in PD remains controversial. Here, we performed a single intracerebroventricular (i.c.v.) infusion of α-syn oligomers (α-SYOs) in mice and evaluated motor and non-motor symptoms. Familiar bedding and vanillin essence discrimination tasks showed that α-SYOs impaired olfactory performance of mice, and decreased TH and dopamine levels in the olfactory bulb early after infusion. The olfactory deficit persisted until 45days post-infusion (dpi). α- SYO-infused mice behaved normally in the object recognition and forced swim tests, but showed increased anxiety-like behavior in the open field and elevated plus maze tests 20 dpi. Finally, administration of α-SYOs induced late motor impairment in the pole test and rotarod paradigms, along with reduced TH and dopamine content in the caudate putamen, 45 dpi. Reduced number of TH-positive cells was also seen in the substantia nigra of α-SYO-injected mice compared to control. In conclusion, i.c.v. infusion of α-SYOs recapitulated some of PD-associated non-motor symptoms, such as increased anxiety and olfactory dysfunction, but failed to recapitulate memory impairment and depressive-like behavior typical of the disease. Moreover, α-SYOs i.c.v. administration induced motor deficits and loss of TH and dopamine levels, key features of PD. Results point to α-syn oligomers as the proximal neurotoxins responsible for early non-motor and motor deficits in PD and suggest that the i.c.v. infusion model characterized here may comprise a useful tool for identification of PD novel therapeutic targets and drug screening. |
| Databáze: | OpenAIRE |
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