21:T427,Aggregation and intracellular deposition of the protein α-synuclein is an underlying characteristic of Parkinson's disease. α-Synuclein assemblies also undergo cell-cell spreading, facilitating propagation of their cellular pathology. Understanding how cellular interactions and uptake of extracellular α-synuclein assemblies depend on their physical attributes is therefore important. We prepared fragmented fluorescently labeled α-synuclein amyloid fibrils of different average lengths (∼80 nm to >1 μm) and compared their interactions with SH-SY5Y cells. We report that fibrils of all lengths, but not monomers, bind avidly to the cell surface. Their uptake is inversely dependent on their average size, occurs via a heparan sulfate dependent endocytic route, and appears to have a size cutoff of ∼400 nm. The uptake of α-synuclein fibrils, but not monomers, correlates with their cytotoxicity as measured by reduction in metabolic activity, strongly suggesting an intracellular basis for α-synuclein fibril toxicity, likely involving endolysosomes.22:T55d,Plaque deposits composed of amyloid-β (Aβ) fibrils are pathological hallmarks of Alzheimer's disease (AD). Although copper ion dyshomeostasis is apparent in AD brains and copper ions are found co-deposited with Aβ peptides in patients' plaques, the molecular effects of copper ion interactions and redox-state dependence on Aβ aggregation remain elusive. By combining biophysical and theoretical approaches, we here show that Cu²⁺ (oxidized) and Cu⁺ (reduced) ions have opposite effects on the assembly kinetics of recombinant Aβ(1-42) into amyloid fibrils in vitro. Cu²⁺ inhibits both the unseeded and seeded aggregation of Aβ(1-42) at pH 8.0. Using mathematical models to fit the kinetic data, we find that Cu²⁺ prevents fibril elongation. The Cu²⁺-mediated inhibition of Aβ aggregation shows the largest effect around pH 6.0 but is lost at pH 5.0, which corresponds to the pH in lysosomes. In contrast to Cu²⁺, Cu⁺ ion binding mildly catalyzes the Aβ(1-42) aggregation via a mechanism that accelerates primary nucleation, possibly via the formation of Cu⁺-bridged Aβ(1-42) dimers. Taken together, our study emphasizes redox-dependent copper ion effects on Aβ(1-42) aggregation and thereby provides further knowledge of putative copper-dependent mechanisms resulting in AD.23:T68b,

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