Natural Compounds May Open New Routes to Treatment of Amyloid Diseases

Abstract

Protein misfolding disorders, such as Alzheimer's disease and Parkinson's disease, have in common that a protein accumulates in an insoluble form in the affected tissue. The process of aggregation follows a mechanism of seeded polymerization. Although the toxic species is still not well defined, the process, rather than the end product, of fibril formation is likely the main culprit in amyloid toxicity. These findings suggest that therapeutic strategies directed against the protein misfolding cascade should focus on depleting aggregation intermediates rather than on large fibrillar aggregates. Recent studies involving natural compounds have suggested new intervention strategies. The polyphenol epi-gallocatechine-3-gallate (EGCG), the main polyphenol in Camilla sinensis, binds directly to a large number of proteins that are involved in protein misfolding diseases and inhibits their fibrillization. Instead, it promotes the formation of stable, spherical aggregates. These spherical aggregates are not cytotoxic, have a lower β-sheet content than fibrils, and do not catalyze fibril formation. Correspondingly, epi-gallocatechine-3-gallate remodels amyloid fibrils into aggregates with the same properties. Derivatives of Orcein, which is a phenoxazine dye that can be isolated from the lichen Roccella tinctoria, form a second promising class of natural compounds. They accelerate fibril formation of the Alzheimer's disease-related amyloid-beta peptide. At the same time these compounds deplete oligomeric and protofibrillar forms of the peptide. These compounds may serve as proof-of-principle for the strategies of promoting and redirecting fibril formation. Both may emerge as two promising new therapeutic approaches to intervening into protein misfolding processes.

Systematic development of small molecules to inhibit specific microscopic steps of Aβ42 aggregation in Alzheimer’s disease

“…Because the presence of abnormal Aβ metabolism can be detected 10-20 years before the onset of AD (12,13), early interventions may be possible before widespread and irreversible neurodegeneration has occurred. Although targeting Aβ accumulation has been pursued as a major potential therapeutic strategy against AD (14)(15)(16)(17), no compound selected for this purpose has yet entered clinical use (18,19).…”

Transthyretin Binding Heterogeneity and Anti-amyloidogenic Activity of Natural Polyphenols and Their Metabolites

“…Polyphenols are the most abundant antioxidant compounds present in human diet, and potential beneficial activities in the prevention of degenerative diseases, including amyloidoses, have been attributed to these molecules (20,21). Previous studies provided evidence for the specific interactions of resveratrol (22) and of some flavonoids (23)(24)(25) with the T4 binding sites of TTR and for their ability to stabilize TTR tetramer and to inhibit fibril formation (23)(24)(25)(26).…”

The Ins and Outs of Nanoparticle Technology in Neurodegenerative Diseases and Cancer

“…Most of the resulting aggregates are highly ordered because they are enriched in crossed β-sheet structures (i.e. amyloid-like polymers) can be stained with dyes such as Congo red or Thioflavin T [99][100][101]. It has been suggested that oligomeric species are the more toxic forms compared to larger aggregates [102].…”

“…However, the bioavailability of EGCG and access to the brain is quite poor [99]. The integration of such a compound into NPs to enhance its delivery to the brain is logically studied [78] and appears to inhibit amyloid aggregates in vitro when incorporated to Tet-1 peptide (a neuron-targeting molecule allowing the bypass of the BBB via a retrograde axonal transport) linked selenium NPs [164].…”

“…The same strategy was chosen using sphingomyelin and cholesterol liposomes functionalized with amyloid-binding acidic lipids such as ganglioside GM-1, phosphatidic acid or cardiolipin in vitro and was shown to alleviate tau pathology acting on the balance between kinases and phosphatases while transposition to an animal model should take in account that GM-1 can cause neuropathies [165]. Curcumin, which can bind amyloid aggregates, as EGCG (the both are actually in clinical trials for a possible AD therapeutic action) is also subjected to NP encapsulation in the aim to enhance its action as a proved PN enhancer compound since it presents a poor bioavailability in vivo [99,[166][167][168][169]] not only in AD context but also in most of the degenerative diseases linked to protein aggregation such as type 2 diabetes [170].…”