Multivariate Effects of Brain Micro-environmental Constituents on Amyloid Proteins

Aberrant accumulation of amyloid proteins into different kinds of aggregates is closely related to a cluster of disorders, called protein misfolding diseases. Various micro-environmental constituents in brains modulate amyloid proteins and have been drawing extensive attention in the field of amyloid study. However, the effects of these micro-environmental constituents in brain such as proteins (chaperone, amyloid, and Apolipoprotein E (ApoE) proteins), lipids, metal ions, pH, and ionic strength, have been only investigated separately, with no consensus achieved. In this thesis work, I studied how different combinations of these micro-environmental constituents affect amyloid proteins. Specifically, the cross-interactions between Apolipoprotein E and various amyloid proteins were reviewed in Chapter 2; the covariant effects of Hsp90/ATP and pH/ionic strength/zinc ions on Aβ40 peptides were investigated in Chapter 3 and Chapter 4, respectively; and how lipid and copper ions modulate alpha-synuclein (α-Syn) protein was studied in Chapter 5. The results are as follows: (1) ApoE interacts with different amyloid proteins and one specific amyloid protein can interact with both ApoE and other amyloid proteins; (2) ATP impedes the inhibitory effect of Hsp90 on Aβ40 fibrillation; (3) pH, salt, and zinc ions possess significantly different effects on Aβ40 fibrillation, depending on the specific combination of these three micro-environmental constituents, and the morphology of Aβ40 aggregates can be modulated by the presence of salt; (4) α-Syn proteins modulate the phase behavior of lipidic cubic phase (LCP) and copper ions at micromolar range counteract the effect of α-Syn on the phase behavior of LCP. These results can, to some extent, explain the discrepancy in this field and draw more attention to the multivariate effects of different micro-environmental constituents in brains on amyloid proteins.