Abstract
The accumulation of α-synuclein (α-syn) in the brain plays a role in synucleinopathies and it is hypothesized to spread in a prion-like fashion between connected brain regions. In the present study, we aim to investigate this spreading in well-characterized sagittal organotypic whole brain slices taken from postnatal wild type (WT) and transgenic mice overexpressing human α-syn under the promoter of proteolipid protein (PLP). Collagen hydrogels were loaded with monomers of human α-syn, as well as human and mouse pre-formed fibrils (PFFs), to allow local application and slow release. The spreading of α-syn was evaluated in different brain regions by immunohistochemistry for total α-syn and α-syn phosphorylated at the serine129 position (α-syn-P). The application of human and mouse PFFs of α-syn caused the aggregation and spreading of α-syn-P in the brain slices, which was pronounced the most at the region of hydrogel application and surrounding striatum, as well as along the median forebrain bundle. The organotypic slices from transgenic mice showed significantly more α-syn pathology than those from WT mice. The present study demonstrates that seeding with α-syn PFFs but not monomers induced intracellular α-syn pathology, which was significantly more prominent in brain slices with α-syn overexpression. This is consistent with the prion-like spreading theory of α-syn aggregates. The sagittal whole brain slices characterized in this study carry the potential to be used as a novel model to study α-syn pathology.
Highlights
Alpha-synuclein (α-syn) is a 140-amino-acid protein that is widely expressed in the brain
Sagittal organotypic brain slices were cultured on semipermeable membrane inserts and adhered well within the first week (Figure 1A)
The brain slices were cultured for 8 further weeks and the aggregation and spreading of α-syn was assessed in five brain regions (Figure 1B,C)
Summary
Alpha-synuclein (α-syn) is a 140-amino-acid protein that is widely expressed in the brain. The accumulation of insoluble α-syn aggregates is the hallmark pathology of synucleinopathies that include Parkinson’s disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Increasing evidence shows that some proteins (e.g., beta-amyloid, tau and α-syn) associated with neurodegenerative diseases such as Alzheimer’s disease or PD follow a characteristic spatiotemporal pattern for spreading in the brain [5]. This spreading hypothesis is based on two main mechanisms, namely, the aggregation of the protein by incorporating the native forms into the fibrils and the spreading over distances
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