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16 pages, 4699 KiB

Open AccessArticle

Effects of Terahertz Radiation on the Aggregation of Alzheimer’s Aβ42 Peptide

by Lei Wang, Yuanyuan Cheng, Wenxia Wang, Jinwu Zhao, Yinsong Wang, Xumei Zhang, Meng Wang, Tianhe Shan and Mingxia He

Int. J. Mol. Sci. 2023, 24(5), 5039; https://doi.org/10.3390/ijms24055039 - 6 Mar 2023

Cited by 1 | Viewed by 1902

Abstract

The pathophysiology of Alzheimer’s disease is thought to be directly linked to the abnormal aggregation of β-amyloid (Aβ) in the nervous system as a common neurodegenerative disease. Consequently, researchers in many areas are actively looking for factors that affect Aβ aggregation. Numerous investigations [...] Read more.

The pathophysiology of Alzheimer’s disease is thought to be directly linked to the abnormal aggregation of β-amyloid (Aβ) in the nervous system as a common neurodegenerative disease. Consequently, researchers in many areas are actively looking for factors that affect Aβ aggregation. Numerous investigations have demonstrated that, in addition to chemical induction of Aβ aggregation, electromagnetic radiation may also affect Aβ aggregation. Terahertz waves are an emerging form of non-ionizing radiation that has the potential to affect the secondary bonding networks of biological systems, which in turn could affect the course of biochemical reactions by altering the conformation of biological macromolecules. As the primary radiation target in this investigation, the in vitro modeled Aβ42 aggregation system was examined using fluorescence spectrophotometry, supplemented by cellular simulations and transmission electron microscopy, to see how it responded to 3.1 THz radiation in various aggregation phases. The results demonstrated that in the nucleation aggregation stage, 3.1 THz electromagnetic waves promote Aβ42 monomer aggregation and that this promoting effect gradually diminishes with the exacerbation of the degree of aggregation. However, by the stage of oligomer aggregation into the original fiber, 3.1 THz electromagnetic waves exhibited an inhibitory effect. This leads us to the conclusion that terahertz radiation has an impact on the stability of the Aβ42 secondary structure, which in turn affects how Aβ42 molecules are recognized during the aggregation process and causes a seemingly aberrant biochemical response. Molecular dynamics simulation was employed to support the theory based on the aforementioned experimental observations and inferences. Full article

(This article belongs to the Special Issue Alzheimer’s Disease: Role and Structure of Soluble Oligomers)

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16 pages, 2292 KiB

Open AccessArticle

Reg-1α, a New Substrate of Calpain-2 Depending on Its Glycosylation Status

by Marie-Christine Lebart, Françoise Trousse, Gilles Valette, Joan Torrent, Morgane Denus, Nadine Mestre-Frances and Anne Marcilhac

Int. J. Mol. Sci. 2022, 23(15), 8591; https://doi.org/10.3390/ijms23158591 - 2 Aug 2022

Viewed by 1540

Abstract

Reg-1α/lithostathine, a protein mainly associated with the digestive system, was previously shown to be overexpressed in the pre-clinical stages of Alzheimer’s disease. In vitro, the glycosylated protein was reported to form fibrils at physiological pH following the proteolytic action of trypsin. However, the [...] Read more.

Reg-1α/lithostathine, a protein mainly associated with the digestive system, was previously shown to be overexpressed in the pre-clinical stages of Alzheimer’s disease. In vitro, the glycosylated protein was reported to form fibrils at physiological pH following the proteolytic action of trypsin. However, the nature of the protease able to act in the central nervous system is unknown. In the present study, we showed that Reg-1α can be cleaved in vitro by calpain-2, the calcium activated neutral protease, overexpressed in neurodegenerative diseases. Using chemical crosslinking experiments, we found that the two proteins can interact with each other. Identification of the cleavage site using mass spectrometry, between Gln⁴ and Thr⁵, was found in agreement with the in silico prediction of the calpain cleavage site, in a position different from the one reported for trypsin, i.e., Arg¹¹-Ile¹² peptide bond. We showed that the cleavage was impeded by the presence of the neighboring glycosylation of Thr⁵. Moreover, in vitro studies using electron microscopy showed that calpain-cleaved protein does not form fibrils as observed after trypsin cleavage. Collectively, our results show that calpain-2 cleaves Reg-1α in vitro, and that this action is not associated with fibril formation. Full article

(This article belongs to the Special Issue Alzheimer’s Disease: Role and Structure of Soluble Oligomers)

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22 pages, 3259 KiB

Open AccessArticle

The Small Molecule GAL-201 Efficiently Detoxifies Soluble Amyloid β Oligomers: New Approach towards Oral Disease-Modifying Treatment of Alzheimer’s Disease

by Hermann Russ, Michele Mazzanti, Chris Parsons, Katrin Riemann, Alexander Gebauer and Gerhard Rammes

Int. J. Mol. Sci. 2022, 23(10), 5794; https://doi.org/10.3390/ijms23105794 - 21 May 2022

Cited by 2 | Viewed by 2298

Abstract

Soluble amyloid β (Aβ) oligomers have been shown to be highly toxic to neurons and are considered to be a major cause of the neurodegeneration underlying Alzheimer’s disease (AD). That makes soluble Aβ oligomers a promising drug target. In addition to eliminating these [...] Read more.

Soluble amyloid β (Aβ) oligomers have been shown to be highly toxic to neurons and are considered to be a major cause of the neurodegeneration underlying Alzheimer’s disease (AD). That makes soluble Aβ oligomers a promising drug target. In addition to eliminating these toxic species from the patients’ brain with antibody-based drugs, a new class of drugs is emerging, namely Aβ aggregation inhibitors or modulators, which aim to stop the formation of toxic Aβ oligomers at the source. Here, pharmacological data of the novel Aβ aggregation modulator GAL-201 are presented. This small molecule (288.34 g/mol) exhibits high binding affinity to misfolded Aβ_1-42 monomers (K_D = 2.5 ± 0.6 nM). Pharmacokinetic studies in rats using brain microdialysis are supportive of its oral bioavailability. The Aβ oligomer detoxifying potential of GAL-201 has been demonstrated by means of single cell recordings in isolated hippocampal neurons (perforated patch experiments) as well as in vitro and in vivo extracellular monitoring of long-term potentiation (LTP, in rat transverse hippocampal slices), a cellular correlate for synaptic plasticity. Upon preincubation, GAL-201 efficiently prevented the detrimental effect on LTP mediated by Aβ_1-42 oligomers. Furthermore, the potential to completely reverse an already established neurotoxic process could also be demonstrated. Of particular note in this context is the self-propagating detoxification potential of GAL-201, leading to a neutralization of Aβ oligomer toxicity even if GAL-201 has been stepwise removed from the medium (serial dilution), likely due to prion-like conformational changes in Aβ_1-42 monomer aggregates (trigger effect). The authors conclude that the data presented strongly support the further development of GAL-201 as a novel, orally available AD treatment with potentially superior clinical profile. Full article

(This article belongs to the Special Issue Alzheimer’s Disease: Role and Structure of Soluble Oligomers)

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17 pages, 7191 KiB

Open AccessArticle

The Interplay of Apoes with Syndecans in Influencing Key Cellular Events of Amyloid Pathology

by Anett Hudák, Katalin Jósvay, Ildikó Domonkos, Annamária Letoha, László Szilák and Tamás Letoha

Int. J. Mol. Sci. 2021, 22(13), 7070; https://doi.org/10.3390/ijms22137070 - 30 Jun 2021

Cited by 6 | Viewed by 2536

Abstract

Apolipoprotein E (ApoE) isoforms exert intricate effects on cellular physiology beyond lipid transport and metabolism. ApoEs influence the onset of Alzheimer’s disease (AD) in an isoform-dependent manner: ApoE4 increases AD risk, while ApoE2 decreases it. Previously we demonstrated that syndecans, a transmembrane proteoglycan [...] Read more.

Apolipoprotein E (ApoE) isoforms exert intricate effects on cellular physiology beyond lipid transport and metabolism. ApoEs influence the onset of Alzheimer’s disease (AD) in an isoform-dependent manner: ApoE4 increases AD risk, while ApoE2 decreases it. Previously we demonstrated that syndecans, a transmembrane proteoglycan family with increased expression in AD, trigger the aggregation and modulate the cellular uptake of amyloid beta (Aβ). Utilizing our previously established syndecan-overexpressing cellular assays, we now explore how the interplay of ApoEs with syndecans contributes to key events, namely uptake and aggregation, in Aβ pathology. The interaction of ApoEs with syndecans indicates isoform-specific characteristics arising beyond the frequently studied ApoE–heparan sulfate interactions. Syndecans, and among them the neuronal syndecan-3, increased the cellular uptake of ApoEs, especially ApoE2 and ApoE3, while ApoEs exerted opposing effects on syndecan-3-mediated Aβ uptake and aggregation. ApoE2 increased the cellular internalization of monomeric Aβ, hence preventing its extracellular aggregation, while ApoE4 decreased it, thus helping the buildup of extracellular plaques. The contrary effects of ApoE2 and ApoE4 remained once Aβ aggregated: while ApoE2 reduced the uptake of Aβ aggregates, ApoE4 facilitated it. Fibrillation studies also revealed ApoE4′s tendency to form fibrillar aggregates. Our results uncover yet unknown details of ApoE cellular biology and deepen our molecular understanding of the ApoE-dependent mechanism of Aβ pathology. Full article

(This article belongs to the Special Issue Alzheimer’s Disease: Role and Structure of Soluble Oligomers)

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16 pages, 1947 KiB

Open AccessArticle

Membrane Interactions Accelerate the Self-Aggregation of Huntingtin Exon 1 Fragments in a Polyglutamine Length-Dependent Manner

by Arnaud Marquette, Christopher Aisenbrey and Burkhard Bechinger

Int. J. Mol. Sci. 2021, 22(13), 6725; https://doi.org/10.3390/ijms22136725 - 23 Jun 2021

Cited by 3 | Viewed by 2018

Abstract

The accumulation of aggregated protein is a typical hallmark of many human neurodegenerative disorders, including polyglutamine-related diseases such as chorea Huntington. Misfolding of the amyloidogenic proteins gives rise to self-assembled complexes and fibres. The huntingtin protein is characterised by a segment of consecutive [...] Read more.

The accumulation of aggregated protein is a typical hallmark of many human neurodegenerative disorders, including polyglutamine-related diseases such as chorea Huntington. Misfolding of the amyloidogenic proteins gives rise to self-assembled complexes and fibres. The huntingtin protein is characterised by a segment of consecutive glutamines which, when exceeding ~ 37 residues, results in the occurrence of the disease. Furthermore, it has also been demonstrated that the 17-residue amino-terminal domain of the protein (htt17), located upstream of this polyglutamine tract, strongly correlates with aggregate formation and pathology. Here, we demonstrate that membrane interactions strongly accelerate the oligomerisation and β-amyloid fibril formation of htt17-polyglutamine segments. By using a combination of biophysical approaches, the kinetics of fibre formation is investigated and found to be strongly dependent on the presence of lipids, the length of the polyQ expansion, and the polypeptide-to-lipid ratio. Finally, the implications for therapeutic approaches are discussed. Full article

(This article belongs to the Special Issue Alzheimer’s Disease: Role and Structure of Soluble Oligomers)

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12 pages, 939 KiB

Open AccessArticle

Anti-Parallel β-Hairpin Structure in Soluble Aβ Oligomers of Aβ40-Dutch and Aβ40-Iowa

by Ziao Fu, William E. Van Nostrand and Steven O. Smith

Int. J. Mol. Sci. 2021, 22(3), 1225; https://doi.org/10.3390/ijms22031225 - 27 Jan 2021

Cited by 8 | Viewed by 2536

Abstract

The amyloid-β (Aβ) peptides are associated with two prominent diseases in the brain, Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA). Aβ42 is the dominant component of cored parenchymal plaques associated with AD, while Aβ40 is the predominant component of vascular amyloid associated [...] Read more.

The amyloid-β (Aβ) peptides are associated with two prominent diseases in the brain, Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA). Aβ42 is the dominant component of cored parenchymal plaques associated with AD, while Aβ40 is the predominant component of vascular amyloid associated with CAA. There are familial CAA mutations at positions Glu22 and Asp23 that lead to aggressive Aβ aggregation, drive vascular amyloid deposition and result in degradation of vascular membranes. In this study, we compared the transition of the monomeric Aβ40-WT peptide into soluble oligomers and fibrils with the corresponding transitions of the Aβ40-Dutch (E22Q), Aβ40-Iowa (D23N) and Aβ40-Dutch, Iowa (E22Q, D23N) mutants. FTIR measurements show that in a fashion similar to Aβ40-WT, the familial CAA mutants form transient intermediates with anti-parallel β-structure. This structure appears before the formation of cross-β-sheet fibrils as determined by thioflavin T fluorescence and circular dichroism spectroscopy and occurs when AFM images reveal the presence of soluble oligomers and protofibrils. Although the anti-parallel β-hairpin is a common intermediate on the pathway to Aβ fibrils for the four peptides studied, the rate of conversion to cross-β-sheet fibril structure differs for each. Full article

(This article belongs to the Special Issue Alzheimer’s Disease: Role and Structure of Soluble Oligomers)

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Review

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14 pages, 20082 KiB

Open AccessReview

Neurotoxic Soluble Amyloid Oligomers Drive Alzheimer’s Pathogenesis and Represent a Clinically Validated Target for Slowing Disease Progression

by Martin Tolar, John Hey, Aidan Power and Susan Abushakra

Int. J. Mol. Sci. 2021, 22(12), 6355; https://doi.org/10.3390/ijms22126355 - 14 Jun 2021

Cited by 73 | Viewed by 15470

Abstract

A large body of clinical and nonclinical evidence supports the role of neurotoxic soluble beta amyloid (amyloid, Aβ) oligomers as upstream pathogenic drivers of Alzheimer’s disease (AD). Recent late-stage trials in AD that have evaluated agents targeting distinct species of Aβ provide compelling [...] Read more.

A large body of clinical and nonclinical evidence supports the role of neurotoxic soluble beta amyloid (amyloid, Aβ) oligomers as upstream pathogenic drivers of Alzheimer’s disease (AD). Recent late-stage trials in AD that have evaluated agents targeting distinct species of Aβ provide compelling evidence that inhibition of Aβ oligomer toxicity represents an effective approach to slow or stop disease progression: (1) only agents that target soluble Aβ oligomers show clinical efficacy in AD patients; (2) clearance of amyloid plaque does not correlate with clinical improvements; (3) agents that predominantly target amyloid monomers or plaque failed to show clinical effects; and (4) in positive trials, efficacy is greater in carriers of the ε4 allele of apolipoprotein E (APOE4), who are known to have higher brain concentrations of Aβ oligomers. These trials also show that inhibiting Aβ neurotoxicity leads to a reduction in tau pathology, suggesting a pathogenic sequence of events where amyloid toxicity drives an increase in tau formation and deposition. The late-stage agents with positive clinical or biomarker data include four antibodies that engage Aβ oligomers (aducanumab, lecanemab, gantenerumab, and donanemab) and ALZ-801, an oral agent that fully blocks the formation of Aβ oligomers at the clinical dose. Full article

(This article belongs to the Special Issue Alzheimer’s Disease: Role and Structure of Soluble Oligomers)

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19 pages, 882 KiB

Open AccessReview

The Toxicity and Polymorphism of β-Amyloid Oligomers

by Ya-ru Huang and Rui-tian Liu

Int. J. Mol. Sci. 2020, 21(12), 4477; https://doi.org/10.3390/ijms21124477 - 24 Jun 2020

Cited by 82 | Viewed by 12357

Abstract

It is widely accepted that β-amyloid oligomers (Aβos) play a key role in the progression of Alzheimer’s disease (AD) by inducing neuron damage and cognitive impairment, but Aβos are highly heterogeneous in their size, structure and cytotoxicity, making the corresponding studies tough to [...] Read more.

It is widely accepted that β-amyloid oligomers (Aβos) play a key role in the progression of Alzheimer’s disease (AD) by inducing neuron damage and cognitive impairment, but Aβos are highly heterogeneous in their size, structure and cytotoxicity, making the corresponding studies tough to carry out. Nevertheless, a number of studies have recently made remarkable progress in the describing the characteristics and pathogenicity of Aβos. We here review the mechanisms by which Aβos exert their neuropathogenesis for AD progression, including receptor binding, cell membrane destruction, mitochondrial damage, Ca²⁺ homeostasis dysregulation and tau pathological induction. We also summarize the characteristics and pathogenicity such as the size, morphology and cytotoxicity of dimers, trimers, Aβ*56 and spherical oligomers, and suggest that Aβos may play a different role at different phases of AD pathogenesis, resulting in differential consequences on neuronal synaptotoxicity and survival. It is warranted to investigate the temporal sequence of Aβos in AD human brain and examine the relationship between different Aβos and cognitive impairment. Full article

(This article belongs to the Special Issue Alzheimer’s Disease: Role and Structure of Soluble Oligomers)

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