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Clusterin in Alzheimer's disease: An amyloidogenic inhibitor of amyloid formation?

2022; Elsevier BV; Volume: 1868; Issue: 7 Linguagem: Inglês

10.1016/j.bbadis.2022.166384

1879-260X

Panagiotis M. Spatharas, Georgia I. Nasi, Paraskevi L. Tsiolaki, Marilena K. Theodoropoulou, Nikolaos Papandreou, Andreas Hoenger, Ioannis P. Trougakos, Vassiliki A. Iconomidou,

Machine Learning in Bioinformatics

Clusterin is a heterodimeric glycoprotein (α- and β-chain), which has been described as an extracellular molecular chaperone. In humans, clusterin is an amyloid-associated protein, co-localizing with fibrillar deposits in several amyloidoses, including Alzheimer's disease. To clarify its potential implication in amyloid formation, we located aggregation-prone regions within the sequence of clusterin α-chain, via computational methods. We had peptide-analogues, which correspond to each of these regions, chemically synthesized and experimentally demonstrated that all of them can form amyloid-like fibrils. We also provide evidence that the same peptide-analogues can inhibit amyloid-β fibril formation, potentially making them appropriate drug candidates for Alzheimer's disease. At the same time, our findings hint that the respective aggregation-prone clusterin regions may be implicated in the molecular mechanism in which clusterin inhibits amyloid formation. Furthermore, we suggest that molecular chaperones with amyloidogenic properties might have a role in the regulation of amyloid formation, essentially acting as functional amyloids.