Pathological α-synuclein accumulation, CSF metabolites changes and brain microstructures in cynomolgus monkeys...

The lack of evidence indicating the accumulation of phosphorylated α-synuclein (P-α-syn), a neuropathological hallmark of Parkinson disease (PD), limits the application of 6-OHDA animal models. In cynomolgus monkeys received unilateral 6-hydroxydopamine (6-OHDA) injection, we identified nigrostriatal dysfunction related behavioral defects, such as the increase of PD score, decrease of locomotor activities, and exhibition of typical rotations. We found the dopaminergic neurons were significantly reduced and had fragmented morphology in substantia nigra (SN). Furthermore, insoluble P-α-syn aggregates were observed. The P-α-syn aggregates were extracellular distributed and had typical morphology of inclusion. Immunofluorescence staining showed that the P-α-syn colocalized with ubiquitin (Ub) and p62. We also found there were more actived astrocytes and microglial in SN and striatum, reflecting neuroinflammations increase in nigrostriatal pathway. At last, to determine the long-term consequence of dopamine (DA) neuron loss induced by 6-OHDA injection, the changes of cerebrospinal fluid (CSF) neurotransmitters over time as well as the brain microstructure alternations were examined. The dopamine-related metabolites were decreased after 6-OHDA injection reflecting dopaminergic neuron loss. The levels of γ-aminobutyric acid (GABA) and acetylcholine (Ach) showed an increasing trend but not significant. By diffusion tensor Magnetic Resonance Imaging (MRI) image scans, the fractional anisotropy (FA) value in the ipsilateral SN and caudate was found to reduce, which indicated neural fiber injury. Therefore, these results suggested that α-syn pathology might participate in process of 6-OHDA injuring DA neurons, and may expand the application of 6-OHDA monkeys on investigations into the pathogenesis of PD.