Nanoscale Structure and Spectroscopic Probing of Aβ1-40 Fibril Bundle Formation

Abstract

Amyloid plaques composed of fibrillar Amyloid-β (Aβ) are hallmarks of Alzheimer's disease. However, Aβ fibrils are morphologically heterogeneous. Conformation sensitive luminescent conjugated oligothiophenes (LCOs) are versatile tools for monitoring such fibril polymorphism in vivo and in vitro. Biophysical methods applied on in vitro generated Aβ fibrils, stained with LCOs with different binding and fluorescence properties, can be used to characterize the Aβ fibrillation in depth, far beyond that possible for in vivo generated amyloid plaques. In this study, in vitro fibrillation of the Aβ1-40 peptide was monitored by time-lapse transmission electron microscopy, LCO fluorescence, and atomic force microscopy. Differences in the LCO binding in combination with nanoscale imaging revealed that spectral variation correlated with fibrils transforming from solitary filaments (Ø~2.5 nm) into higher order bundled structures (Ø~5 nm). These detailed in vitro experiments can be used to derive data that reflects the heterogeneity of in vivo generated Aβ plaques observed by LCO fluorescence. Our work provides new structural basis for targeted drug design and molecular probe development for amyloid imaging.

Controlling the Functional Properties of Oligothiophene Crystalline Nano/Microfibers via Tailoring of the Self‐Assembling Molecular Precursors

“…We expect that the search for novel “noncovalent interactional algorithms” will be particularly fruitful in the field of thiophene oligomers, which are very versatile functional materials, fluorescent, and conductive, with astonishing recognition capabilities via nonbonded interactions even inside living cells and organisms . They can physiologically co‐assemble with specific proteins inside live cells[15e] and are p‐type semiconductors but can acquire n‐type charge transport properties by sulfur functionalization with oxygen .…”

Aggregated Aβ1-42 Is Selectively Toxic for Neurons, Whereas Glial Cells Produce Mature Fibrils with Low Toxicity in Drosophila

“…This ratio varies depending on fibrillar structure. A high ratio indicates a mature bundled fibrillar structures, whereas a low ratio indicates immature and single-filament fibril structures (Nyströ m et al, 2013;Psonka-Antonczyk et al, 2016). Ab1-42 expressed in fly neurons, by both strong and weak drivers, showed a distinct morphology, appearing mostly in ringtangle-like structures ( Figure 4A, inset), with a predominance of the h-FTAA fluorescence spectrum (low 499/540 nm ratio) (Figure 4B).…”

The Importance of Macrophages, Lipid Membranes and Seeding in Experimental AA Amyloidosis

“…Both AEF1 and AEF2 were highly positive for hFTAA, which detects immature amyloid deposits as well as mature. However, only AEF1 was positive for qFTAA, which previously has been shown to bind mature amyloid with rigid and ordered structure [82,83,215]. Interestingly, the fibrillar morphology, of AEF1 was significantly different from a grid of fresh AEF1, prepared 21 years earlier, as studied by TEM (Paper III).…”