On the nature of mixed neurodegenerative amyloidopathies

Sammanfattning: lzheimer's disease (AD) and Parkinson's disease (PD) are the most common neurodegenerative diseases in the world. However, the underlying cause of the development of these diseases is not yet well understood. It has been possible to identify common denominators for AD and PD. Up to 50% of AD cases show similar pathology observed in PD, e.g. aggregation of the amyloid-beta (Aβ) and alpha-synuclein (α-syn) proteins. These include aggregates of amyloid proteins in the form of senile plaques (Aβ) and Lewy bodies (α-syn). However, the molecular mechanisms of protein aggregation are yet to be discovered. In this thesis, we generated novel models to experimentally study protein aggregation in PD and AD: (1) induced pluripotent stem cells (iPSC) expressing a familial PD-linked mutation in the GBA gene, (2) idiopathic and familial PD patient-derived midbrain spheroids, and (3) a mouse model of mixed amyloidosis of aggregated α-syn and Aβ. Furthermore, we developed a novel approach to study protein aggregation by combining spectroscopy methods such as Optical Photothermal Infrared (O-PTIR) and synchrotron-based X-ray fluorescence (S-XRF). We utilized various biochemical methods to analyze levels of Aβ and α-syn in brain cells of AD and PD patients. In addition, we imaged cells with spectroscopy methods using visible, infrared (IR), and X-ray radiation to characterize the aggregates structure and distribution. Our novel methodological approach allows for imaging of the same samples from different perspectives by studying cells with light of different wavelength. The cell models could be beneficial to develop patient-specific treatments, as well as study early, pre-symptomatic, molecular changes in patient brain cells. Likewise, our novel mouse model of mixed proteinopathies could further provide insight into early molecular mechanisms triggering amyloid aggregation related to AD and PD.