2021 · Oren — Amyloid β structural polymorphism, associated toxicity and therapeutic strategies.
Super-Abstract
This comprehensive review covers the many different structural forms (polymorphs) of amyloid-β (Aβ) — the protein fragment central to Alzheimer's disease — how they form, why some are more toxic than others, and what therapeutic strategies are being pursued to interfere with their aggregation. Molecular hydrogen is not a primary subject of this paper; the hydrogen bonds discussed are intramolecular protein bonds, not H₂ therapy. (Cellular and Molecular Life Sciences, 2021.)
Commentary
Aβ aggregation is central to Alzheimer's disease pathology, but the relationship between specific Aβ conformations and neurotoxicity has remained stubbornly unclear. Oren et al. synthesize a large body of multidisciplinary literature to map the on- and off-fibrillar assembly pathways, the environmental factors (pH, ions, lipids, proteins) that determine which polymorph forms, and how each form's hydrogen-bond network and hydrophobic interactions determine its stability and toxicity. The review also surveys candidate inhibitors and inducers of Aβ oligomerization — small molecules, peptides, antibodies — as potential Alzheimer's therapeutics. The mention of hydrogen bonds in this context refers exclusively to intramolecular and inter-chain bonding within Aβ protein structures, not to molecular hydrogen (H₂) as a therapeutic gas. This review's relevance to H₂ medicine is marginal; it is included here as scientific background on Aβ neurotoxicity mechanisms relevant to neurodegeneration research.
Key quotes
- „The conformations of the different Aβ species are stabilized by intra- and inter-molecular hydrogen bonds and by electrostatic and hydrophobic interactions“ — the structural basis of Aβ polymorphism — these are protein hydrogen bonds, not H₂ gas
- „a large variety of amyloid-β (Aβ) oligomeric species, differing in molecular weight, conformation and morphology“ — core finding: Aβ is not a single entity but a complex population of species
- „we provide an overview of the existing inhibitors (or inducers) of Aβ oligomerization that serve as potential therapeutics for neurodegenerative diseases.“ — scope of the therapeutic section
Our assessment
This is a narrative review of Aβ structural biology and aggregation inhibitor research. It does not study molecular hydrogen as a therapeutic agent. The mention of „hydrogen bonds“ relates to protein chemistry, not H₂ gas. The review is a valuable reference for the neuroscience of amyloid disease and therapeutic targeting of Aβ aggregation, but has very limited direct relevance to H₂-medicine. Readers interested in H₂ and neurodegeneration should seek studies that specifically test H₂ administration in Alzheimer's models.
Study design
- Type: comprehensive narrative review · Scope: Aβ oligomeric species, assembly mechanisms, toxicity determinants, therapeutic inhibitors/inducers · H₂ relevance: marginal (protein hydrogen bonds only; no H₂ therapy studied)
- Conclusion: Aβ structural heterogeneity underlies variable neurotoxicity; multiple inhibitor classes show promise in vitro and in preclinical models; clinical translation remains a major challenge
Abstract
A review of the multidisciplinary scientific literature reveals a large variety of amyloid-β (Aβ) oligomeric species, differing in molecular weight, conformation and morphology. These species, which may assemble via either on- or off-aggregation pathways, exhibit differences in stability, function and neurotoxicity, according to different experimental settings. The conformations of the different Aβ species are stabilized by intra- and inter-molecular hydrogen bonds and by electrostatic and hydrophobic interactions, all depending on the chemical and physical environment (e.g., solvent, ions, pH) and interactions with other molecules, such as lipids and proteins. This complexity and the lack of a complete understanding of the relationship between the different Aβ species and their toxicity is currently dictating the nature of the inhibitor (or inducer)-based approaches that are under development for interfering with (or inducing) the formation of specific species and Aβ oligomerization, and for interfering with the associated downstream neurotoxic effects. Here, we review the principles that underlie the involvement of different Aβ oligomeric species in neurodegeneration, both in vitro and in preclinical studies. In addition, we provide an overview of the existing inhibitors (or inducers) of Aβ oligomerization that serve as potential therapeutics for neurodegenerative diseases. The review, which covers the exciting studies that have been published in the past few years, comprises three main parts: 1) on- and off-fibrillar assembly mechanisms and Aβ structural polymorphism; 2) interactions of Aβ with other molecules and cell components that dictate the Aβ aggregation pathway; and 3) targeting the on-fibrillar Aβ assembly pathway as a therapeutic approach.
Source & links
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