Amyloid Proteins in Neurodegenerative Disease – Role of Extrinsic Modifiers
Self-assembly of disease-associated proteins into fibrillar homopolymers, so-called “amyloid fibrils” is a pathological hallmark of several debilitating human disorders, including Alzheimer’s disease (AD) and Parkinson’s disease (PD). AD and PD are associated with the formation of amyloid fibrils from the proteins amyloid-β (Aβ) and α-syn (α-syn), in the extracellular and intracellular space, respectively. In Aβ pathogenesis, there are different molecules such as metal ions and lipids that can interact with Aβ, and affect amyloid fibril formation but also other important pathological features such as cellular uptake, which contributes to the intracellular build-up of aggregates that precede the deposition of extracellular plaques.
This thesis describes my research on the effects of different extrinsic modulators, mainly metals and lipids, in Aβ and α-syn aggregation, as well as in the cellular uptake of Aβ. I showed that Cu2+ inhibits Aβ(1-42) amyloid formation by impairment of the fibril elongation mechanism whereas Cu+ catalysed primary nucleation, indicating an important role of copper redox chemistry in AD. I further showed that Cu2+, and also Zn2+, whilst acting aggregation inhibitory, enhance Aβ(1-42) uptake and thereby contribute to other pathological effects, including prion-like cell-to-cell propagation.
In a second part of my work, I explored the effect of lipid vesicles of biological and synthetic origin on the Aβ(1-42) aggregation process. I found that cell-derived extracellular vesicles impede the elongation process and induce the formation of amyloid fibrils with distinct morphology. Synthetic lipid vesicles, on the other hand, were found to have diverse effects on the Aβ(1-42) aggregation rate and mechanism and I showed that both lipid chemistry and the physical properties of the bilayers they participate in, contribute to the modulatory role of membrane in Aβ(1-42) aggregation.
To analyse physical attributes of amyloid fibrils, I developed a nanofluidic-based method for visualization of single amyloid fibrils in solution and used it to compare persistence lengths of different fibril types as well as within samples, addressing the concept of polymorphism. Lastly, my work has contributed to the understanding of how graphene-based nanoparticles can modulate amyloid formation by interfering with both primary nucleation and secondary processes in aggregation.
Keywords: Alzheimer’s disease, protein aggregation, amyloid fibril, amyloid-β, Aβ(1-42), α-synuclein, extracellular vesicles, lipid vesicle, kinetics, nanofluidics, fluorescence microscopy, atomic force microscopy
Chalmers, Life sciences, Kemisk biologi
Vesa Halipi, Nima Sasanian, Julia Feng, Jing Hu, Quentin Lubart, David Bernson, Daniel van Leeuwen, Doryaneh Ahmadpour, Emma Sparr and Elin K. Esbjörner. Inhibition of Aβ(1-42) aggregation by cell-derived extracellular vesicles
Nima Sasanian, Vesa Halipi, Mikaela Sjögren, Johannes Bengtsson, David Bernson and Elin K. Esbjörner. Ganglioside GM1 slows down Aβ(1-42) fibril formation by a primary nucleation inhibitory mechanism that is modulated by lipid membrane sphingomyelin and cholesterol
Redox-Dependent Copper Ion Modulation of Amyloid-β (1-42) Aggregation In Vitro
Biomolecules,; Vol. 10(2020)p. 1-19
Artikel i vetenskaplig tidskrift
Nima Sasanian, Andrea Ramnath, Shadi Rahimi, Daniel van Leeuwen, Emelie Wesén, David Bernson, Ivan Mijakovic and Elin K. Esbjörner. Copper and zinc enhance the intracellular accumulation, cell-cell transfer, and cytotoxicity of Alzheimer’s diseases peptide Aβ(1-42)
Nima Sasanian, Rajhans Sharma, Quentin Lubart, Sriram KK, Marziyeh Ghaeidamini, Kevin D. Dorfman, Elin K. Esbjörner and Fredrik Westerlund. Probing physical properties of amyloid fibrils using nanofluidic channels
Graphene oxide sheets and quantum dots inhibit alpha-synuclein amyloid formation by different mechanisms
Nanoscale,; Vol. 12(2020)p. 19450-19460
Artikel i vetenskaplig tidskrift
Nanovetenskap och nanoteknik
Biokemi och molekylärbiologi
Doktorsavhandlingar vid Chalmers tekniska högskola. Ny serie: 5238
KA salen, Chemistry building, Kemigården 4
Opponent: Astrid Gräslund, , Stockholm Universitet, Stockholm.