Clusterin in Alzheimer’s disease: an amyloidogenic inhibitor of amyloid formation

Abstract

AbstractClusterin 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 of each region 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. These findings elucidate parts of the molecular mechanism in which clusterin inhibits amyloid formation. At the same time, they hint that molecular chaperones with amyloidogenic properties might have a role in the regulation of amyloid formation, essentially acting as functional amyloids.