Investigating the link between Amyloid-beta and alpha-Synuclein pathology
Collaborative project with REDSHIFTbio
Lewy Body (LB) diseases are one of the most common neurodegenerative disorders, second to Alzheimer’s disease (AD), and comprise of Parkinson’s disease (PD), PD Dementia (PDD) and Dementia with LBs (DLB). They are defined by the presence of alpha-synuclein (α-syn) inclusions but frequently present a mixed pathology of amyloid beta (Aβ) and tau as well. Patient cases with this mixed pathology have increased levels of protein aggregates, faster progression and worse clinical outcome, not only in LB diseases but also in AD cases with LBs. Mouse models that are transgenic for both Aβ and α-syn recapitulate the more severe disease course observed in humans and together implies a synergistic relationship between Aβ and α-syn in neurodegeneration. The initial discovery of α-syn within amyloid plaques in AD and DLB brains suggested that this may occur by a direct interaction between Aβ and α-syn in disease that promotes their aggregation, a hypothesis that has been investigated in vitro in a number of cell-free biochemical assays. Aβ and α-syn interactions are limited in healthy conditions because they do not exist in the same subcellular location, and are likely to resemble a pathological state in which compromised neuronal function or cell damage leads to elevated levels of extracellular α-syn. This increases the availability of α-syn for interaction with Aβ, particularly Aβ40 which is the major species in plasma and CSF.
In particular, the structural influence of α-syn on Aβ was demonstrated by Mandal et al.2006 using NMR spectroscopy. 2 hr co-incubation of Aβ with α-syn at physiological pH was sufficient to induce structural changes in both Aβ40 and Aβ42 peptides. The α-syn was found to induce greater structural changes in the more aggregate prone Aβ42 compared to the more soluble Aβ40 peptide even after 15 hrs of incubation. This study was conducted in an artificial lipid based environment using equal concentrations of Aβ and α-syn, but questions still remain regarding the structural dynamics of Aβ-α-syn interactions when extracellular levels of the proteins are altered in disease.
The aim of this study is to test the hypothesis that disruption in the levels of α-syn leads to alterations in Aβ40 towards an aggregate prone state in the extracellular compartment. This study will incorporate novel REDSHIFTbio technology which uses microfluidic modulation spectroscopy (MMS) to measure real time changes in the secondary structure of proteins with exceptionally high sensitivity and accuracy in real time.The use of background subtraction enables proteins to be analyzed in complex buffers with high fidelity enabling structural changes of aSyn and Aβ to be monitored under physiological conditions. This study may reveal novel targets for drug design to prevent toxic interactions between proteins.