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

Age-related diseases of the brain, e.g. dementias and prion disease, are caused by a variety of different factors. Some of these diseases share also common changes and common clinical problems, for example speech, memory and orientation disabilities. Some of these diseases are being currently regarded as possible infectious. This project was introduced to investigate common modifiers of these diseases which could explain the propensity for infection or not. We want to find specific markers and pathways that are changed in Alzheimer's disease mouse models, which lead to that amyloid-beta can be transmitted and induce disease in other organisms. We will use a novel approach (neutron-labelled isotopes of carbon - 13C) which make it possible to visualise these pathways and locations that are possibly involved in AD, CJD and CWD. We have performed a number of biological experiments and establishment of methods and are currently measuring ultra-low amount of Abeta in tissue from the experimental mice using nanoLC-massspectrometry to determine locations and storage of Abeta after intraperitoneal injection. We can detect Abeta in the liver and lymphknodes at specific time points but never in the brain.

Våre resultater påviser at Alzheimer sykdom er ikke overførbar og dermed ikke tilhører sykdomsgruppen 'prionensykdommer'. Vi antar derfor at Alzheimer sykdom er ikke en risiko for parørende eller pleiepersoner.

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 beta-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, TGFbeta1 knockout, and LRP1 knockout mice) and isotope-labelled amyloids to detect the spatial and temporal distribution behaviour of peripherally injected amyloid-beta (Abeta). 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 Abeta towards the brain. Additionally, we are interested to decipher sequence variants of A? 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.