Amyloid Beta-peptide (25-35) (human)

Epigenetic axis of SNHG19/miR-137/TNFAIP1 modulates amyloid beta peptide 25-35-induced SH-SY5Y cytotoxicity

Aims: In this study, the authors hypothesized that, in an in vitro Alzheimer's disease model, the epigenetic axis of SNHG19/hsa-miR-137 functionally regulates amyloid beta peptide 25-35 (Aβ25-35)-induced SH-SY5Y cytotoxicity. Methods: Dual luciferase activity assay demonstrated that SNHG19 could directly bind hsa-miR-137. In Aβ25-35-treated SH-SY5Y cells, SNHG19 was upregulated and hsa-miR-137 downregulated. Results: SNHG19 knockdown ameliorated Aβ25-35-induced SH-SY5Y cytotoxicity, then reversed by secondary hsa-miR-137 downregulation. TNFAIP1 was dynamically regulated by Aβ25-35 and gene modifications in SH-SY5Y cells. Finally, upregulation of TNFAIP1 reversed the protective effect of SNHG19 knockdown on Aβ25-35-induced cytotoxicity. Conclusions: The authors concluded that the epigenetic axis of SNHG19/hsa-miR-137/TNFAIP1 may functionally regulate Aβ25-35-induced SH-SY5Y cytotoxicity, thus making it a potential molecular target for Alzheimer's disease treatment.

Tachykinin Neuropeptides and Amyloid β (25-35) Assembly: Friend or Foe?

Amyloid β (Aβ) protein is responsible for Alzheimer's disease, and one of its important fragments, Aβ(25-35), is found in the brain and has been shown to be neurotoxic. Tachykinin neuropeptides, including Neuromedin K (NK), Kassinin, and Substance P, have been reported to reduce Aβ(25-35)'s toxicity in cells even though they share similar primary structures with Aβ(25-35). Here, we seek to understand the molecular mechanisms of how these peptides interact with Aβ(25-35) and to shed light on why some peptides with similar primary structures are toxic and others nontoxic. We use both experimental and computational methods, including ion mobility mass spectrometry and enhanced-sampling replica-exchange molecular dynamics simulations, to study the aggregation pathways of Aβ(25-35), NK, Kassinin, Substance P, and mixtures of the latter three with Aβ(25-35). NK and Substance P were observed to remove the higher-order oligomers (i.e., hexamers and dodecamers) of Aβ(25-35), which are related to its toxicity, although Substance P did so more slowly. In contrast, Kassinin was found to promote the formation of these higher-order oligomers. This result conflicts with what is expected and is elaborated on in the text. We also observe that even though they have significant structural homology with Aβ(25-35), NK, Kassinin, and Substance P do not form hexamers with a β-sheet structure like Aβ(25-35). The hexamer structure of Aβ(25-35) has been identified as a cylindrin, and this structure has been strongly correlated to toxic species. The reasons why the three tachykinin peptides behave so differently when mixed with Aβ(25-35) are discussed.

Curcumin and Homotaurine Suppress Amyloid-β25-35 Aggregation in Synthetic Brain Membranes

Amyloid-β (Aβ) peptides spontaneously aggregate into β- and cross-β-sheets in model brain membranes. These nanometer sized can fuse into larger micrometer sized clusters and become extracellular and serve as nuclei for further plaque and fibril growth. Curcumin and homotaurine represent two different types of Aβ aggregation inhibitors. While homotaurine is a peptic antiaggregant that binds to amyloid peptides, curcumin is a nonpeptic molecule that can inhibit aggregation by changing membrane properties. By using optical and fluorescent microscopy, X-ray diffraction, and UV-vis spectroscopy, we study the effect of curcumin and homotaurine on Aβ_25-35 aggregates in synthetic brain membranes. Both molecules partition spontaneously and uniformly in membranes and do not lead to observable membrane defects or disruption in our experiments. Both curcumin and homotaurine were found to significantly reduce the number of small, nanoscopic Aβ aggregates and the corresponding β- and cross-β-sheet signals. While a number of research projects focus on potential drug candidates that target Aβ peptides directly, membrane-lipid therapy explores membrane-mediated pathways to suppress peptide aggregation. Based on the results obtained, we conclude that membrane active drugs can be as efficient as peptide targeting drugs in inhibiting amyloid aggregation in vitro.

Conformations and biological activities of amyloid beta peptide 25-35

Amyloid-beta (Abeta) peptide is commonly found in human Alzheimer's disease (AD) brain and is the main component of Alzheimer amyloid plaques. The predominant forms of Abeta in the human brain are Abeta(1-40) and Abeta(1-42), but Abeta(25-35) fragment, physiologically present in elderly people, is the more toxic region and has been recently found to play a relevant role in AD, due to its peculiar aggregation properties. In this work, we review the current understanding on the conformations and biological activity of Abeta(25-35) exploring aggregation, cytotoxic and neurodegenerative properties of this fundamental Abeta fragment, in order to provide an effective starting point to better approach a pathology spread and problematic as AD.

Structure of amyloid β25-35 in lipid environment and cholesterol-dependent membrane pore formation

The amyloid β (Aβ) peptide and its shorter variants, including a highly cytotoxic Aβ_25-35 peptide, exert their neurotoxic effect during Alzheimer's disease by various mechanisms, including cellular membrane permeabilization. The intrinsic polymorphism of Aβ has prevented the identification of the molecular basis of Aβ pore formation by direct structural methods, and computational studies have led to highly divergent pore models. Here, we have employed a set of biophysical techniques to directly monitor Ca²⁺-transporting Aβ_25-35 pores in lipid membranes, to quantitatively characterize pore formation, and to identify the key structural features of the pore. Moreover, the effect of membrane cholesterol on pore formation and the structure of Aβ_25-35 has been elucidated. The data suggest that the membrane-embedded peptide forms 6- or 8-stranded β-barrel like structures. The 8-stranded barrels may conduct Ca²⁺ ions through an inner cavity, whereas the tightly packed 6-stranded barrels need to assemble into supramolecular structures to form a central pore. Cholesterol affects Aβ_25-35 pore formation by a dual mechanism, i.e., by direct interaction with the peptide and by affecting membrane structure. Collectively, our data illuminate the molecular basis of Aβ membrane pore formation, which should advance both basic and clinical research on Alzheimer's disease and membrane-associated pathologies in general.