Intrastriatal alpha-synuclein fibrils in monkeys: spreading, imaging and neuropathological changes

Several studies have demonstrated that intrastriatal injections of fibrillar alpha-synuclein in rodent brain induced a Parkinson's disease-like propagation of Lewy body pathology with significant nigrostriatal neurodegeneration. This study evaluated the pathological features when exogenous alpha-synuclein preformed fibrils were injected into the putamen of non-human primates. Eight cynomolgus monkeys received unilateral intraputamen injections of alpha-synuclein preformed fibrils and four monkeys received sham surgery. Monkeys were assessed with I-123-PE2I single-photon emission computerized tomography scans targeting the dopamine transprter at baseline, 3, 6, 9, 12, and 15 months. Imaging revealed a robust increase in dopamine transporter binding, an effect confirmed by port-mortem immunohistochemical analyses, suggesting that upregulation of dopamine transporter occurs as part of an early pathological process. Histochemistry and immunohistochemistry revealed that alpha-synuclein preformed fibrils injections into the putamen induced intraneuronal inclusions positive for phosphorylated alpha-synuclein in ipsilateral substantia nigra and adjacent to the injection site. alpha-Synuclein inclusions were thioflavin-S-positive suggesting that the inclusions induced by alpha-synuclein preformed fibrils exhibited pathological properties similar to amyloid-like Lewy body pathology in Parkinson's disease brains. The alpha-synuclein preformed fibrils resulted in Lewy pathology in the ipsilateral substantia nigra with significant reduction (-29.30%) of dopaminergic neurons as compared with controls. Nigral neurons with alpha-synuclein inclusions exhibited a phenotypic downregulation of the dopamine markers tyrosine hydroxylase and Nurr1. Taken together, our findings demonstrate that alpha-synuclein preformed fibrils induce a synucleinopathy in non-human primates with authentic Lewy pathology and nigrostriatal changes indicative of early Parkinson's disease.