Project: Propagation behaviour of peripheral amyloid-beta towards brain structures: effects of the blood-brain barrier

Acronym	PROP-AD (Reference Number: 28)
Duration	01/01/2017 - 31/12/2019
Project Topic	(1) Scientific abstract of the project Protein aggregation strongly depends on amino acid sequence and overall folding behaviour. In the light of Creutzfeld-Jacob disease (CJD) it has been discussed whether or not similar folding and aggregation mechanisms are found in other neurodegenerative diseases without being infectious but transmissible as CJD. Amyloidoses are a group of proteopathies in the peripheral organs and the central nervous system with specific aggregation behaviour leading to beta-sheeted aggregates of specific proteins, which can be stained using Congo Red dye. By definition these aggregates show bi-fringence in polarised light, and only then they are called amyloidoses. During the recent years it has been discussed whether β-sheeted species can serve a folding matrix and also to propagate disease-related, misfolded/misaggregated proteins. In the proposed project, we plan to analyse how specifically-labelled proteins/amyloids can reach the brain from the periphery (peritoneum, spleen, gut/intestinal lymph nodes) using MS isotope tags.Special emphasis lies thereby on recently discovered clearance mechanisms. We will utilize a set of new mouse models with functional abrogation at the blood-brain barrier (humanized ABC transporter, TGFβ1 knockout, and LRP1 knockout mice) and isotope-labelled amyloids to detect the spatial and temporal distribution behaviour of peripherally injected amyloid-β (Aβ). Using innovative technologies, including focused laser capture dissection linked to mass spectrometry and mass spectrometry imaging, and isotope mass-labelling we will be able to detect routes of propagation of peripheral Aβ towards the brain. Additionally, we are interested to decipher sequence variants of Aβ with enhanced or reduced propagation propensity. We assume that the results of this project will have broad impact on the understanding of the propagation behaviour of peripheral amyloids and will help to assess whether there is a common risk for the population by peripherally spreading or administered amyloids to advance towards the brain. We can directly transfer our findings to the patient’s situation in providing kinetics data of periphery to brain propagation of Aβ, its dependency in transmembrane transport and possible routes of interference for therapeutic purposes. (2) The projects relevance for the aims of the call The call ‘Advanced experimental models of neurodegenerative diseases’ focusses on the creation of novel mouse models that may help to understand and predict disease. We plan to generate new models that are abrogated in one or more transport mechanisms at the blood-brain barrier to decipher the precise route of peripheral Aβ towards the brain. At the present time, it is not clear now how Aβ propagates towards the brain. Even do direct evidence was found to address the questions whether peripheral Aβ leads to a matrix-like folding mechanism in the brain at all. First proof from Mathias Jucker’s group at the Hertie-Institute Tübingen/Germany showed indirect evidence. We want to use newly developed techniques in combining new mouse models and mass-specific labelling of Aβ. The experiments will enable us to gather highly relevant information for the pathogenesis of neurodegenerative diseases, especially for sporadic disease entities. We will gather insights into genetic heterogeneity, the characterization of progressive neurodegeneration and protein aggregate deposition/propagation; we will use novel innovative molecular imaging techniques and hopefully gain a deeper understanding of proteotoxicity mechanisms. The newly developed mouse models can also be used to investigate other neurodegenerative diseases with protein/peptide aggregates and brain deposition.
Network	JPco-fuND
Call	Neurodegenerative diseases: risk and protective factors, longitudinal cohort approaches and advanced experimental models

Project partner

Number	Name	Role	Country
1	University of Oslo	Coordinator	Norway
2	University of Mainz	Partner	Germany
3	University of Tel Aviv	Partner	Israel
4	Karolinska Institutet Stockholm	Partner	Sweden
5	University of Helsinki	Partner	Finland