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.

Amyloid fibrils are formed when soluble proteins misfold into highly ordered insoluble fibrillar aggregates and affect various organs and tissues. The deposition of amyloid fibrils is the main hallmark of a group of disorders, called amyloidoses. Curiously, fibril deposition has been also recorded as a complication in a number of other pathological conditions, including well-known neurodegenerative or endocrine diseases. To date, amyloidoses are roughly classified, owing to their tremendous heterogeneity. In this work, we introduce AmyCo, a freely available collection of amyloidoses and clinical disorders related to amyloid deposition. AmyCo classifies 75 diseases associated with amyloid deposition into two distinct categories, namely 1) amyloidosis and 2) clinical conditions associated with amyloidosis. Each database entry is annotated with the major protein component (causative protein), other components of amyloid deposits and affected tissues or organs. Database entries are also supplemented with appropriate detailed annotation and are referenced to ICD-10, MeSH, OMIM, PubMed, AmyPro and UniProtKB databases. To our knowledge, AmyCo is the first attempt towards the creation of a complete and an up-to-date repository, containing information about amyloidoses and diseases related to amyloid deposition. The AmyCo web interface is available at http://bioinformatics.biol.uoa.gr/amyco.

Today, Alzheimer’s disease (AD)—the most common neurodegenerative disorder, which affects 50 million people—remains incurable. Several studies suggest that one of the main pathological hallmarks of AD is the accumulation of abnormal amyloid beta (Aβ) aggregates; therefore, many therapeutic approaches focus on anti-Aβ aggregation inhibitors. Taking into consideration that plant-derived secondary metabolites seem to have neuroprotective effects, we attempted to assess the effects of two flavones—eupatorin and scutellarein—on the amyloidogenesis of Aβ peptides. Biophysical experimental methods were employed to inspect the aggregation process of Aβ after its incubation with each natural product, while we monitored their interactions with the oligomerized Aβ through molecular dynamics simulations. More importantly, we validated our in vitro and in silico results in a multicellular organismal model—namely, Caenorhabditis elegans—and we concluded that eupatorin is indeed able to delay the amyloidogenesis of Aβ peptides in a concentration-dependent manner. Finally, we propose that further investigation could lead to the exploitation of eupatorin or its analogues as potential drug candidates.

Alzheimer’s disease (AD) is the most common form of dementia. Given the link between oxidative stress and AD, many studies focus on the identification of natural antioxidants against AD. Although their antioxidant capacity is important, increasing data suggest that additional activities are related to their beneficial effects, including properties against amyloid beta (Aβ) aggregation. Sideritis spp. (mountain tea) extracts possess not only antioxidant activity but also other bioactivities that confer neuroprotection. Although various Sideritis spp. extracts have been extensively studied, there are scarce data on S. clandestina subsp. peloponnesiaca (SCP) phytochemical composition and neuroprotective potential, while nothing is known of the responsible compounds. Given that SCP is a weaker antioxidant compared to other Sideritis spp., here, we investigated its potential beneficial properties against Aβ aggregation. We characterized different SCP extracts and revealed their anti-aggregation activity by taking advantage of established C. elegans AD models. Importantly, we identified two pure compounds, namely, sideridiol and verbascoside, being responsible for the beneficial effects. Furthermore, we have revealed a potential anti-Aβ aggregation mechanism for sideridiol. Our results support the use of mountain tea in the elderly against dementia and demonstrate the activity of sideridiol against Aβ aggregation that could be exploited for drug development.