Amyloid Proteins in Neurodegenerative Disease – Role of Extrinsic Modifiers
Doctoral thesis, 2023

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

KA salen, Chemistry building, Kemigården 4
Opponent: Astrid Gräslund, , Stockholm Universitet, Stockholm.


Nima Sasanian

Chalmers, Life Sciences, Chemical Biology

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

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

Neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) are devastating conditions that are caused by the death of nerve cells and that lead to progressive development of disease-specific symptoms such as dementia or problem with movement and motoric functions. Many neurodegenerative diseases share a common molecular trait. They are associated with the formation of protein clumps in and around neurons in the brain. The protein clumps consist of fibrillar (thread-like) aggregates of disease-specific proteins called amyloid fibrils. The previous general belief was that these protein clumps caused cell death. Although, this belief has changed over time and developed thanks to extensive research, amyloid fibril formation remains the main hallmarks of AD and PD and the most common basis for the development of new medicines. The inside and surroundings of cells are heavily packed with numerous different molecules including various lipids, metal ions and proteins which are essential for cells to stay alive and fulfill their duties. Amyloid forming proteins are in constant contact with these different molecules which can affect their localization and their potency to aggregate and form amyloid fibrils. In this thesis, I have studied how metal ions modulate the cellular uptake and aggregation of a protein called amyloid-β (Aβ) which is associated with AD. Moreover, I have explored the effect of a special type of lipids vesicles that cells secrete to communicate and made various synthetic lipid vesicles with well-defined lipid compositions to understand the role of membranes in AD pathology. My work contributes new molecular level information on the fine-tuned molecular regulation of protein aggregation in the brain and thus to the understanding of the roles of Aβ and other proteins in neurodegenerative disease.

Areas of Advance

Nanoscience and Nanotechnology

Subject Categories

Biochemistry and Molecular Biology


Nano Technology



Doktorsavhandlingar vid Chalmers tekniska högskola. Ny serie: 5238



KA salen, Chemistry building, Kemigården 4

Opponent: Astrid Gräslund, , Stockholm Universitet, Stockholm.

More information

Latest update

2/6/2023 8