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

Clusterin is a heterodimeric glycoprotein (alpha- and beta-chain), which has been described as an extracellular mo-lecular 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 alpha-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-beta 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.

Automated summary

Clusterin is identified as a glycoprotein involved in amyloid formation and has aggregation-prone regions that can form amyloid-like fibrils while also inhibiting amyloid-beta fibril formation. These findings suggest a potential role of clusterin in the molecular mechanism of inhibiting amyloid formation and indicate a possible involvement of molecular chaperones with amyloidogenic properties in regulating amyloid formation.