scholarly journals Amyloid beta: structure, biology and structure-based therapeutic development

2017 ◽  
Vol 38 (9) ◽  
pp. 1205-1235 ◽  
Author(s):  
Guo-fang Chen ◽  
Ting-hai Xu ◽  
Yan Yan ◽  
Yu-ren Zhou ◽  
Yi Jiang ◽  
...  
Keyword(s):  
Amyloid Beta ◽  
Therapeutic Development ◽  
Beta Structure

The Importance of Understanding Amylin Signaling Mechanisms for Therapeutic Development in the Treatment of Alzheimer’s Disease

2020 ◽  
Vol 26 (12) ◽  
pp. 1345-1355 ◽  
Author(s):  
Spencer Servizi ◽  
Rachel R. Corrigan ◽  
Gemma Casadesus
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Beta ◽  
Signaling Cascades ◽  
Complex Nature ◽  
Amyloid Accumulation ◽  
Therapeutic Development ◽  
Critical Insight ◽  
The Brain

Type II Diabetes (T2D) is a major risk factor for Alzheimer’s Disease (AD). These two diseases share several pathological features, including amyloid accumulation, inflammation, oxidative stress, cell death and cognitive decline. The metabolic hormone amylin and amyloid-beta are both amyloids known to self-aggregate in T2D and AD, respectively, and are thought to be the main pathogenic entities in their respective diseases. Furthermore, studies suggest amylin’s ability to seed amyloid-beta aggregation, the activation of common signaling cascades in the pancreas and the brain, and the ability of amyloid beta to signal through amylin receptors (AMYR), at least in vitro. However, paradoxically, non-aggregating forms of amylin such as pramlintide are given to treat T2D and functional and neuroprotective benefits of amylin and pramlintide administration have been reported in AD transgenic mice. These paradoxical results beget a deeper study of the complex nature of amylin’s signaling through the several AMYR subtypes and other receptors associated with amylin effects to be able to fully understand its potential role in mediating AD development and/or prevention. The goal of this review is to provide such critical insight to begin to elucidate how the complex nature of this hormone’s signaling may explain its equally complex relationship with T2D and mechanisms of AD pathogenesis.

scholarly journals Spectroscopic investigation of the effect of polyphenolic compounds on the amyloid-[beta] protein

2017 ◽  
Author(s):  
◽  
Brittany L. Hagenhoff
Keyword(s):  
Amyloid Beta ◽  
Rosmarinic Acid ◽  
Nordihydroguaiaretic Acid ◽  
Polyphenolic Compounds ◽  
Beta Sheet ◽  
Amyloid Beta Protein ◽  
Final State ◽  
Deep Ultraviolet ◽  
Beta Structure ◽  
Ultraviolet Resonance Raman

Aggregation of the amyloid-[beta] (A[beta]) protein is associated with the development of Alzheimer's disease. A[beta] is a 39-43 residue cleavage product of the amyloid precursor protein (APP). A[beta] aggregates to produce insoluble plaques in the brain, which are composed of cross [beta]-sheet structured fibrils. Various polyphenolic compounds, both naturally occurring and synthetic, have been shown to interfere with A[beta] aggregation. To evaluate the ability of specific polyphenols to prevent A[beta] aggregation, this investigation utilized nordihydroguaiaretic acid, curcumin, rosmarinic acid, resveratrol, piceatannol, and diethylstilbestrol. These polyphenols differ in the number of ring substituents and the atom linker between the rings. The interaction of A[beta] with the polyphenolic compounds was analyzed using circular dichroism (CD) and deep ultraviolet resonance Raman (dUVRR) spectroscopies. The polyphenols diethylstilbestrol, resveratrol, and piceatannol have increasing numbers of hydroxyl substituents on their rings, having two, three, and four respectively. It was found that with increasing number of hydroxyl ring substituents, the protein remained predominantly disordered and prevented formation of [beta]-structure in the protein and aided in the destabilization of pre-formed A[beta] fibrils. Decreasing the number of hydroxyl substituents increases the likelihood of [beta]-sheet formation, prevented destabilization of pre-formed A[beta] fibrils, and induced loss of stability of the protein. The polyphenols nordihydroguaiaretic acid, curcumin, and rosmarinic acid have increasing polarity respectively in the chain linker between the phenolic rings. Each of these polyphenols have four ring substituents and have four to six atoms in their chain linker. It was found that with increasing the polarity of the linker, the protein had a greater tendency to form a [beta]-structure, however pre-formed A[beta] fibrils were destabilized efficiently by all three polyphenols. Though a nonpolar chain linker pushed fibrillar protein toward a more disordered structure initially, the final state was similar regardless of added polyphenol.

scholarly journals Arginine and Arginine-Rich Peptides as Modulators of Protein Aggregation and Cytotoxicity Associated With Alzheimer’s Disease

2021 ◽  
Vol 14 ◽  
Author(s):  
Somayra S. A. Mamsa ◽  
Bruno P. Meloni
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Aggregation ◽  
Amyloid Beta ◽  
Beneficial Effects ◽  
Therapeutic Development ◽  
Therapeutic Compounds ◽  
Tau Aggregation ◽  
Excitotoxic Cell Death

A substantial body of evidence indicates cationic, arginine-rich peptides (CARPs) are effective therapeutic compounds for a range of neurodegenerative pathologies, with beneficial effects including the reduction of excitotoxic cell death and mitochondrial dysfunction. CARPs, therefore, represent an emergent class of promising neurotherapeutics with multimodal mechanisms of action. Arginine itself is a known chaotrope, able to prevent misfolding and aggregation of proteins. The putative role of proteopathies in chronic neurodegenerative diseases such as Alzheimer’s disease (AD) warrants investigation into whether CARPs could also prevent the aggregation and cytotoxicity of amyloidogenic proteins, particularly amyloid-beta and tau. While monomeric arginine is well-established as an inhibitor of protein aggregation in solution, no studies have comprehensively discussed the anti-aggregatory properties of arginine and CARPs on proteins associated with neurodegenerative disease. Here, we review the structural, physicochemical, and self-associative properties of arginine and the guanidinium moiety, to explore the mechanisms underlying the modulation of protein aggregation by monomeric and multimeric arginine molecules. Arginine-rich peptide-based inhibitors of amyloid-beta and tau aggregation are discussed, as well as further modulatory roles which could reduce proteopathic cytotoxicity, in the context of therapeutic development for AD.

Peptide–surfactant interactions: Consequences for the amyloid-beta structure

2012 ◽  
Vol 420 (1) ◽  
pp. 136-140 ◽  
Author(s):  
Sandra Rocha ◽  
Joana A. Loureiro ◽  
Gerald Brezesinski ◽  
Maria do Carmo Pereira
Keyword(s):  
Amyloid Beta ◽  
Surfactant Interactions ◽  
Beta Structure

Ruthenium(II)–arene complexes with chelating quinoline ligands as anti-amyloid agents

2021 ◽  
pp. 1-7
Author(s):  
Cade J. Meiss ◽  
Paige J. Bothwell ◽  
Michael I. Webb
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Metal Ions ◽  
Amyloid Beta ◽  
The Other ◽  
Soluble Form ◽  
Aβ Peptide ◽  
Arene Complexes ◽  
Therapeutic Development ◽  
Neurotoxic Agent

Recent recognition of the soluble form of the amyloid-beta (Aβ) peptide as a neurotoxic agent in Alzheimer’s disease (AD) has spurred the development of agents to target this species. Because Aβ is known to chelate metal ions in solution, metal-based therapeutics are uniquely suited to exploit this affinity, where coordination to Aβ has been shown to impact the neurotoxicity of the peptide. Ruthenium(II)–arene complexes are unique candidates for evaluation, as one face of the molecule is blocked by the hydrophobic arene ring, while coordination to the Aβ peptide can occur on the other side of the molecule. We have prepared and evaluated two Ru(II)–arene complexes with chelating quinoline-based ligands, Ru1 and Ru2, for their respective anti-amyloid abilities. Although both complexes decreased the aggregation of soluble Aβ, Ru1 displayed promise in disrupting formed aggregates of the peptide. These findings represent an exciting new avenue for therapeutic development in AD, where both sides of the aggregation equilibrium are affected.

Crystalline order to a resolution of 4.7 A in the sheath of Methanospirilium hungatii: A cross-beta structure

1984 ◽  
Vol 42 ◽  
pp. 214-215
Author(s):  
Murray Stewart ◽  
T.J. Beveridge ◽  
D. Sprott
Keyword(s):  
Cell Wall ◽  
Single Layer ◽  
Uranyl Acetate ◽  
Optical Diffraction ◽  
Tube Axis ◽  
Basic Subunit ◽  
Beta Structure ◽  
Diffraction Patterns ◽  
Protein Treatment ◽  
General Appearance

The archaebacterium Methanospirillum hungatii has a sheath as part of its cell wall which is composed mainly of protein. Treatment with dithiothreitol or NaOH released the intact sheaths and electron micrographs of this material negatively stained with uranyl acetate showed flattened hollow tubes, about 0.5 μm diameter and several microns long, in which the patterns from the top and bottom were superimposed. Single layers, derived from broken tubes, were also seen and were more simply analysed. Figure 1 shows the general appearance of a single layer. There was a faint axial periodicity at 28.5 A, which was stronger at irregular multiples of 28.5 A (3 and 4 times were most common), and fine striations were also seen at about 3° to the tube axis. Low angle electron diffraction patterns (not shown) and optical diffraction patterns (Fig. 2) from these layers showed a complex meridian (as a result of the irregular nature of the repeat along the tube axis) which showed a clear maximum at 28.5 A, consistent with the basic subunit spacing.

Proteolytic processing of the amyloid-beta protein precursor of Alzheimer's disease

2002 ◽  
Vol 38 ◽  
pp. 37-49 ◽  
Author(s):  
Janelle Nunan ◽  
David H Small
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Beta ◽  
Alternative Pathway ◽  
Protein A ◽  
Proteolytic Processing ◽  
Gamma Secretase ◽  
Amyloid Beta Protein ◽  
Protein Precursor ◽  
Amyloid Beta Protein Precursor

The proteolytic processing of the amyloid-beta protein precursor plays a key role in the development of Alzheimer's disease. Cleavage of the amyloid-beta protein precursor may occur via two pathways, both of which involve the action of proteases called secretases. One pathway, involving beta- and gamma-secretase, liberates amyloid-beta protein, a protein associated with the neurodegeneration seen in Alzheimer's disease. The alternative pathway, involving alpha-secretase, precludes amyloid-beta protein formation. In this review, we describe the progress that has been made in identifying the secretases and their potential as therapeutic targets in the treatment or prevention of Alzheimer's disease.

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