Objective: Development of a fast and progressive Parkinson’s disease (PD) model in rat

Background: α-Synuclein is a common link between sporadic and familial PD. Rodent PD models based on α-synuclein overexpression have been extremely helpful in elucidating the molecular pathology of disease. However, most of these models are extremely slow to develop and require unrealistically high amounts of α-synuclein to elicit disease features. 

Methods: Female SD rats were injected with a low dose of AAV6-α-syn in substantia nigra (SN) to express monomeric α-synuclein. After 4 weeks, when the α-synuclein is fully expressed, sonicated pre formed fibrils of α-synuclein were injected in same spot. Some rats received either fibrils or AAV6-α-syn only. These rats were histologically evaluated at 3, 12 and 24 weeks post fibril injection.

Results: Fibrils and AAV6-α-syn alone group showed only 10-30% loss of TH positive cells in SN at 3 and 12 weeks. It took either of them 24 weeks to escalate this loss to 50%. However, the combination significantly accelerated this cell loss displaying 55% decrease in just 3 week. Further worsening of this cell loss was relatively slower and reached around 65% after 24 weeks. In contrast, TH fiber density in striatum decreased more gradually changing from 60% at 3 weeks to 40% at 24 weeks in the combination group.  Similar to cell loss, fiber density loss was much more slower in the fibrils or AAV6-α-syn alone groups. Further, a large number of neurons in the combination group expressed phosphorylated α-synuclein (p-syn), which is a marker for aggregated α-synuclein. These aggregates were dense, mature and spread through the nucleus, cytoplasm and dendrites at all time points. In comparison, AAV6-α-syn only group displayed diffuse cytoplasmic occurrence and small puncta in nucleus. Fibrils only group displayed far fewer aggregates occurring mostly in cytoplasm. This combination also elicited neuroinflammation, causing 2-fold increase in the number IBA-1 positive glial cells, which was not observed in other groups.

Conclusions: Ability of fibrils seeds to nucleate the aggregation of monomeric α-synuclein enhanced the pathological process both in time and intensity. Activation of neuroinflammation could be the additional mechanism acting to enhance pathology.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/modeling-parkinsons-disease-pathology-by-combined-injection-of-fibrilar-and-monomeric-%ce%b1-synuclein-in-rat-brain/