Session Time: 12:30pm-2:00pm
Location: Exhibit Hall located in Hall B, Level 2
Objective: Our aim was to test if α-synclein aggregation drives neuronal demise and microglial activation in a murine model of induced-α-synucleinopathy.
Background: Pathological α-synuclein aggregates in the brain are a PD hallmark. Brain α-synuclein aggregation and spreading can be modelled in rodents. Microglial activation is also an early event in PD. However, it is unclear whether it is the α-syncuclein aggregation process itself, or another process, that drives PD-associated neurodegeneration and microgliosis. Understanding these pathological events is an important step toward identifying therapeutic targets.
Methods: C57Bl6/J Mice were injected unilaterally in the striatum with 10µg of sonicated recombinant murine α-synuclein fibrils (to induce α-synucleinopathy), or with PBS (control). After 3 months, brains were prepared for immunohistology, electron microscopy, or dopamine measurement. Dopaminergic neurons number and fibre density, α-synuclein aggregates, microglial activation and synaptic integrity were quantified on digital images of antibody stained brain sections.
Results: Numerous synuclein aggregates were found ipsilaterally (striatum, Subst. Nigra (SN), cortex, amygdala) and contralaterally (cortex, amygadala). In contrast, neurodegeneration and microgliosis were found in brain regions with, but also in brain regions without aggregates. Thus, a slight but significant (15%) decrease in the number of tyrosine-hydroxylase (TH) positive neurons was found in the ipsilateral SN (with aggregates) and the contralateral SN (without aggregates). Both sides showed also prominent microgliosis. The hippocampus, which was completely devoid of aggregates, showed profound synapse degeneration and microgliosis on both sides. The cortex, which had numerous aggregates, also showed profound degeneration of synapses and microgliosis on both sides. The striatum showed loss of dopamine and of TH-positive fibres only ipsilaterally. Further analyses, such as Electron Microscopy, are in progress.
Conclusions: These results show that presence of aggregates does not necessarily coincide with neurodegeneration or microgliosis in a murine model of induced α-synuclein seeding/spreading, indicating that α-synuclein aggregation is not, or at least not always, the major driver of PD-related pathological events. Other α-synuclein entities, such as oligomers, may be responsible for these events.
To cite this abstract in AMA style:P. Garcia, W. Wemheuer, S. Brioschi, A. Masuch, E. Masliah, V. Koziel, T. Pillot, E. Koncina, C. Jaeger, A. Weihofen, R. Balling, K. Biber, M. Buttini. Neurodegeneration and microgliosis are independent of α-synuclein aggregation in a mouse model of "prion-like" α-synuclein speading [abstract]. Mov Disord. 2016; 31 (suppl 2). https://www.mdsabstracts.org/abstract/neurodegeneration-and-microgliosis-are-independent-of-synuclein-aggregation-in-a-mouse-model-of-prion-like-synuclein-speading/. Accessed November 29, 2023.
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