The amyloid fibril formation by α -synuclein is a hallmark of various neurodegenerative disorders, most notably Parkinson’s disease. Epigallocatechin gallate (EGCG) has been reported to be an efficient inhibitor of amyloid formation by numerous proteins, among them α -synuclein. Here, we show that this applies only to a small region of the relevant parameter space, in particular to solution conditions where EGCG readily oxidizes, and we find that the oxidation product is a much more potent inhibitor compared to the unmodified EGCG. In addition to its inhibitory effects, EGCG and its oxidation products can under some conditions even accelerate α -synuclein amyloid fibril formation through facilitating its heterogeneous primary nucleation. Furthermore, we show through quantitative seeding experiments that, contrary to previous reports, EGCG is not able to re-model α -synuclein amyloid fibrils into seeding-incompetent structures. Taken together, our results paint a complex picture of EGCG as a compound that can under some conditions inhibit the amyloid fibril formation of α -synuclein, but the inhibitory action is not robust against various physiologically relevant changes in experimental conditions. Our results are important for the development of strategies to identify and characterize promising amyloid inhibitors.

Alzheimer’s disease (AD) is a severe neurodegenerative pathology with no effective treatment known. Toxic amyloid-β peptide (Aβ) oligomers play a crucial role in AD pathogenesis. All- d -Enantiomeric peptide D3 and its derivatives were developed to disassemble and destroy cytotoxic Aβ aggregates. One of the D3-like compounds is approaching phase II clinical trials; however, high-resolution details of its disease-preventing or pharmacological actions are not completely clear. We demonstrate that peptide D3 stabilizing Aβ monomer dynamically interacts with the extracellular juxtamembrane region of a membrane-bound fragment of an amyloid precursor protein containing the Aβ sequence. MD simulations based on NMR measurement results suggest that D3 targets the amyloidogenic region, not compromising its α-helicity and preventing intermolecular hydrogen bonding, thus creating prerequisites for inhibition of early steps of Aβ conversion into β-conformation and its toxic oligomerization. An enhanced understanding of the D3 action molecular mechanism facilitates development of effective AD treatment and prevention strategies.

The human lateral geniculate body (LGB) with its six sickle shaped layers (lam) represents the principal thalamic relay nucleus for the visual system. Cytoarchitectonic analysis serves as the groundtruth for multimodal approaches and studies exploring its function. This technique, however, requires experienced knowledge about human neuroanatomy and is costly in terms of time. Here we mapped the six layers of the LGB manually in serial, histological sections of the BigBrain, a high-resolution model of the human brain, whereby their extent was manually labeled in every 30th section in both hemispheres. These maps were then used to train a deep learning algorithm in order to predict the borders on sections in-between these sections. These delineations needed to be performed in 1 µm scans of the tissue sections, for which no exact cross-section alignment is available. Due to the size and number of analyzed sections, this requires to employ high-performance computing. Based on the serial section delineations, high-resolution 3D reconstruction was performed at 20 µm isotropic resolution of the BigBrain model. The 3D reconstruction shows the shape of the human LGB and its sublayers for the first time at cellular precision. It represents a use case to study other complex structures, to visualize their shape and relationship to neighboring structures. Finally, our results could provide reference data of the LGB for modeling and simulation to investigate the dynamics of signal transduction in the visual system.

The amyloid fibril formation by $\alpha$-synuclein is a hallmark of various neurodegenerative disorders, most notably Parkinson's disease. Epigallocatechin gallate (EGCG) has been reported to be an efficient aggregation inhibitor of numerous proteins, among them $\alpha$-synuclein. Here we show that this applies only to a small region of relevant parameter space and that under some conditions, EGCG can even accelerate α-synuclein amyloid fibril formation through facilitating its heterogeneous primary nucleation. Furthermore, we show through quantitative seeding experiments that contrary to previous reports, EGCG is not able to re-model α-synuclein amyloid fibrils into seeding-incompetent structures. Taken together, our results paint a complex picture of EGCG as a compound that can under some conditions inhibit the amyloid fibril formation of α-synuclein, but the inhibitory action is not robust against various relevant changes in experimental conditions. Our results are important for the development of strategies to identify and characterise promising amyloid inhibitors.