Lysosomal proteolysis of amyloid beta is impeded by fibrils grown in both acidic and neutral pH environments

BioRxiv : the Preprint Server for Biology
T. R. Lambeth, Ryan R. Julian

Abstract

Aggregation of amyloid-beta (A) into extracellular plaques is a well-known hallmark of Alzheimers disease (AD). Similarly, autophagic vacuoles, autophagosomes, and other residual bodies within dystrophic neurites, though more difficult to detect, are characteristic features of AD. To explore the potential intersection between these observations, we conducted experiments to assess whether A fibril formation disrupts lysosomal proteolysis. Fibrils constituted from either A 1-40 or A 1-42 were grown under both neutral and acidic pH. The extent of proteolysis by individual cathepsins (L, D, B, and H) was monitored by both thioflavin T fluorescence and liquid-chromatography combined with mass spectrometry. The results show that all A fibrils are resistant to cathepsin digestion, with significant amounts of undigested material remaining for samples of fibrils grown in both neutral and acidic pH. Further analysis revealed that the neutral-grown fibrils are proteolytically resistant throughout the sequence, while the acid-grown fibrils prevented digestion primarily in the C-terminal portion of the sequence. Fibrils grown from A 1-42 are generally more resistant to degradation compared to A 1-40. Overall, the results indicate that A fib...Continue Reading

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