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Amyloid-β: Structure, Function, and Pathophysiological Significance in Neurodegenerative Diseases 2.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 January 2023) | Viewed by 37242

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Prof. Dr. Masashi Tanaka

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Department of Physical Therapy, Health Science University, 7187 Kodachi, Fujikawaguchiko-machi, Minamitsuru-gun, Yamanashi 401-0380, Japan
Interests: amyloid-beta; dementia; type 2 diabetes; innate immune system; inflammation; microglia; obesity
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Prof. Dr. Kenjiro Ono

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Department of Neurology, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa 920-8640, Japan
Interests: neurology; dementia; Alzheimer’s disease; Lewy body diseases; amyloid, oligomer; protein aggregation
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Dr. Satoshi Saito

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Department of Neurology, National Cerebral and Cardiovascular Center, 6-1 Kishibe-Shimmachi, Osaka 564-8565, Japan
Interests: Alzheimer's disease; cerebral amyloid angiopathy; small vessel disease; treatment; translational research
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue is a continuation of our previous Special Issue “Amyloid-β: Structure, Function, and Pathophysiological Significance in Neurodegenerative Diseases” (https://0-www-mdpi-com.brum.beds.ac.uk/journal/ijms/special_issues/Ab).

The prevalence of dementia is increasing exponentially worldwide; therefore, its predictive markers and effective treatments should be urgently developed. Considerable studies have revealed the pathological roles of amyloid-β (Aβ) in the development and progression of dementia, namely: Aβ aggregates fibril formation, accumulates senile plaques and blood vessels in the brain, and exhibits cytotoxic effects on neurons and cerebrovascular endothelial cells. These conditions lead to neuronal and vascular injury, thereby resulting in neurodegenerative diseases, such as Alzheimer’s disease (AD) and cerebral amyloid angiopathy, as major causes of dementia. These findings highlight the significance of Aβ as a therapeutic target for dementia, although a new drug focusing on Aβ for the treatment of AD has not yet been developed over the past 15 years. Conversely, recent advances in basic and clinical studies on Aβ and neurodegenerative diseases further reinforce the importance of targeting Aβ and identify the potential novel therapeutic strategies for Aβ-related cognitive impairment.

Here, IJMS sets up this Special Issue focusing on the current understanding and future research directions regarding the structure, function, and pathological significance of Aβ in neurodegenerative diseases. We warmly welcome original manuscripts, review articles, case reports, and commentaries relating to this hot topic.

Prof. Dr. Masashi Tanaka
Prof. Dr. Kenjiro Ono
Dr. Satoshi Saito
Guest Editors

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Keywords

Alzheimer’s disease
amyloid-β
cerebral amyloid angiopathy
fibril formation
microglia
neurodegeneration
predictive markers
treatment

Related Special Issue

Amyloid-β: Structure, Function, and Pathophysiological Significance in Neurodegenerative Diseases in International Journal of Molecular Sciences (16 articles)

Published Papers (12 papers)

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Research

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19 pages, 3947 KiB

Open AccessArticle

The Curcumin Derivative GT863 Protects Cell Membranes in Cytotoxicity by Aβ Oligomers

by Yutaro Momma, Mayumi Tsuji, Tatsunori Oguchi, Hideaki Ohashi, Tetsuhito Nohara, Naohito Ito, Ken Yamamoto, Miki Nagata, Atsushi Michael Kimura, Shiro Nakamura, Yuji Kiuchi and Kenjiro Ono

Int. J. Mol. Sci. 2023, 24(4), 3089; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24043089 - 04 Feb 2023

Cited by 2 | Viewed by 1553

Abstract

In Alzheimer’s disease (AD), accumulation of amyloid β-protein (Aβ) is one of the major mechanisms causing neuronal cell damage. Disruption of cell membranes by Aβ has been hypothesized to be the important event associated with neurotoxicity in AD. Curcumin has been shown to reduce Aβ-induced toxicity; however, due to its low bioavailability, clinical trials showed no remarkable effect on cognitive function. As a result, GT863, a derivative of curcumin with higher bioavailability, was synthesized. The purpose of this study is to clarify the mechanism of the protective action of GT863 against the neurotoxicity of highly toxic Aβ oligomers (Aβo), which include high-molecular-weight (HMW) Aβo, mainly composed of protofibrils in human neuroblastoma SH-SY5Y cells, focusing on the cell membrane. The effect of GT863 (1 μM) on Aβo-induced membrane damage was assessed by phospholipid peroxidation of the membrane, membrane fluidity, membrane phase state, membrane potential, membrane resistance, and changes in intracellular Ca²⁺ ([Ca²⁺]i). GT863 inhibited the Aβo-induced increase in plasma-membrane phospholipid peroxidation, decreased membrane fluidity and resistance, and decreased excessive [Ca²⁺]i influx, showing cytoprotective effects. The effects of GT863 on cell membranes may contribute in part to its neuroprotective effects against Aβo-induced toxicity. GT863 may be developed as a prophylactic agent for AD by targeting inhibition of membrane disruption caused by Aβo exposure. Full article

(This article belongs to the Special Issue Amyloid-β: Structure, Function, and Pathophysiological Significance in Neurodegenerative Diseases 2.0)

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16 pages, 4101 KiB

Open AccessArticle

A Comparative Study between Lycorine and Galantamine Abilities to Interact with AMYLOID β and Reduce In Vitro Neurotoxicity

by Arian Kola, Stefania Lamponi, Francesco Currò and Daniela Valensin

Int. J. Mol. Sci. 2023, 24(3), 2500; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24032500 - 28 Jan 2023

Cited by 5 | Viewed by 1988

Abstract

Galantamine is a natural alkaloid extracted from the Amaryllidaceae plants and is used as the active ingredient of a drug approved for the treatment of the early stages of Alzheimer’s disease. It mainly acts as an acetylcholinesterase (AChE) inhibitor, increasing concentrations of the acetylcholine neurotransmitter. Recent cellular studies have also shown the ability of galantamine to protect SH-SY5Y cell lines against amyloid-β (Aβ)-induced toxicity. Such investigations have supported and validated further in-depth studies for understanding the chemical and molecular features associated with galantamine-protective abilities. In addition to galantamine, other natural alkaloids are known to possess AChE inhibitory activity; among them lycorine has been extensively investigated for its antibacterial, anti-inflammatory and antitumoral activities as well. Despite its interesting biological properties, lycorine’s neuroprotective functions against Aβ-induced damages have not been explored so far. In this research study, the ability of galantamine and lycorine to suppress Aβ-induced in vitro neuronal toxicity was evaluated by investigating the chemical interactions of the two alkaloids with Aβ peptide. A multi-technique spectroscopic analysis and cellular cytotoxicity assays were applied to obtain new insights on these molecular associations. The comparison between the behaviors exhibited by the two alkaloids indicates that both compounds possess analogue abilities to interact with the amyloidogenic peptide and protect cells. Full article

(This article belongs to the Special Issue Amyloid-β: Structure, Function, and Pathophysiological Significance in Neurodegenerative Diseases 2.0)

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11 pages, 2271 KiB

Open AccessArticle

Monitoring the Conformational Changes of the Aβ(25−35) Peptide in SDS Micelles: A Matter of Time

by Angelo Santoro, Michela Buonocore, Manuela Grimaldi, Enza Napolitano and Anna Maria D’Ursi

Int. J. Mol. Sci. 2023, 24(2), 971; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24020971 - 04 Jan 2023

Cited by 1 | Viewed by 1261

Abstract

Alzheimer’s disease is a neurodegenerative disease characterized by the formation of amyloid plaques constituted prevalently by amyloid peptides. Due to the well-known challenges related to the study in solution of these peptides, several membrane-mimicking systems such as micelle constituted by detergent—i.e., DPC and SDS—have been deeply investigated. Additionally, the strategy of studying short fragments instead of the full-length peptide turned out to be advantageous in exploring the structural properties of the different moieties in Aβ in order to reproduce its pathologic effects. Several studies reveal that among Aβ fragments, Aβ(25−35) is the shortest fragment able to reproduce the aggregation process. To enrich the structural data currently available, in the present work we decided to evaluate the conformational changes adopted by Aβ(25−35) in SDS combining CD and NMR spectroscopies at different times. From the solved structures, it emerges that Aβ(25−35) passes from an unordered conformation at the time of the constitution of the system to a more ordered and energetically favorable secondary structure at day 7, which is kept for 2 weeks. These preliminary data suggest that a relatively long time affects the kinetic in the aggregation process of Aβ(25−35) in a micellar system, favoring the stabilization and the formation of a soluble helix conformation. Full article

(This article belongs to the Special Issue Amyloid-β: Structure, Function, and Pathophysiological Significance in Neurodegenerative Diseases 2.0)

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26 pages, 5141 KiB

Open AccessArticle

Internalized Amyloid-β (1-42) Peptide Inhibits the Store-Operated Calcium Entry in HT-22 Cells

by Joana Poejo, Yolanda Orantos-Aguilera, Francisco Javier Martin-Romero, Ana Maria Mata and Carlos Gutierrez-Merino

Int. J. Mol. Sci. 2022, 23(20), 12678; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232012678 - 21 Oct 2022

Cited by 6 | Viewed by 1895

Abstract

Dysregulation in calcium signaling pathways plays a major role in the initiation of Alzheimer’s disease (AD) pathogenesis. Accumulative experimental evidence obtained with cellular and animal models, as well as with AD brain samples, points out the high cytotoxicity of soluble small oligomeric forms of amyloid-β peptides (Aβ) in AD. In recent works, we have proposed that Aβ-calmodulin (CaM) complexation may play a major role in neuronal Ca²⁺ signaling, mediated by CaM-binding proteins (CaMBPs). STIM1, a recognized CaMBP, plays a key role in store-operated calcium entry (SOCE), and it has been shown that the SOCE function is diminished in AD, resulting in the instability of dendric spines and enhanced amyloidogenesis. In this work, we show that 2 and 5 h of incubation with 2 μM Aβ(1-42) oligomers of the immortalized mouse hippocampal cell line HT-22 leads to the internalization of 62 ± 11 nM and 135 ± 15 nM of Aβ(1-42), respectively. Internalized Aβ(1-42) oligomers colocalize with the endoplasmic reticulum (ER) and co-immunoprecipitated with STIM1, unveiling that this protein is a novel target of Aβ. Fluorescence resonance energy transfer measurements between STIM1 tagged with a green fluorescent protein (GFP) and Aβ(1-42)-HiLyte™-Fluor555 show that STIM1 can bind nanomolar concentrations of Aβ(1-42) oligomers at a site located close to the CaM-binding site in STIM1. Internalized Aβ(1-42) produced dysregulation of the SOCE in the HT-22 cells before a sustained alteration of cytosolic Ca²⁺ homeostasis can be detected, and is elicited by only 2 h of incubation with 2 μM Aβ(1-42) oligomers. We conclude that Aβ(1-42)-induced SOCE dysregulation in HT-22 cells is caused by the inhibitory modulation of STIM1, and the partial activation of ER Ca²⁺-leak channels. Full article

(This article belongs to the Special Issue Amyloid-β: Structure, Function, and Pathophysiological Significance in Neurodegenerative Diseases 2.0)

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20 pages, 4042 KiB

Open AccessArticle

Combined Treatment with Curcumin and Ferulic Acid Suppressed the Aβ-Induced Neurotoxicity More than Curcumin and Ferulic Acid Alone

by Hideaki Ohashi, Mayumi Tsuji, Tatsunori Oguchi, Yutaro Momma, Tetsuhito Nohara, Naohito Ito, Ken Yamamoto, Miki Nagata, Atsushi Michael Kimura, Yuji Kiuchi and Kenjiro Ono

Int. J. Mol. Sci. 2022, 23(17), 9685; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23179685 - 26 Aug 2022

Cited by 5 | Viewed by 1872

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease that leads to progressive cognitive decline. Several effective natural components have been identified for the treatment of AD. However, it is difficult to obtain conclusive evidence on the safety and effectiveness of natural components, because a variety of factors are associated with the progression of AD pathology. We hypothesized that a therapeutic effect could be achieved by combining multiple ingredients with different efficacies. The purpose of this study was thus to evaluate a combination treatment of curcumin (Cur) and ferulic acid (FA) for amyloid-β (Aβ)-induced neuronal cytotoxicity. The effect of Cur or FA on Aβ aggregation using thioflavin T assay was confirmed to be inhibited in a concentration-dependent manner by Cur single or Cur + FA combination treatment. The effects of Cur + FA on the cytotoxicity of human neuroblastoma (SH-SY5Y) cells induced by Aβ exposure were an increase in cell viability, a decrease in ROS and mitochondrial ROS, and repair of membrane damage. Combination treatment showed an overall higher protective effect than treatment with Cur or FA alone. These results suggest that the combined action mechanisms of Cur and FA may be effective in preventing and suppressing the progression of AD. Full article

(This article belongs to the Special Issue Amyloid-β: Structure, Function, and Pathophysiological Significance in Neurodegenerative Diseases 2.0)

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11 pages, 2713 KiB

Open AccessCommunication

Ionic Environment Affects Biomolecular Interactions of Amyloid-β: SPR Biosensor Study

by Erika Hemmerová, Tomáš Špringer, Zdeňka Krištofiková and Jiří Homola

Int. J. Mol. Sci. 2020, 21(24), 9727; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21249727 - 20 Dec 2020

Cited by 6 | Viewed by 1836

Abstract

In early stages of Alzheimer’s disease (AD), amyloid beta (Aβ) accumulates in the mitochondrial matrix and interacts with mitochondrial proteins, such as cyclophilin D (cypD) and 17β-hydroxysteroid dehydrogenase 10 (17β-HSD10). Multiple processes associated with AD such as increased production or oligomerization of Aβ affect these interactions and disbalance the equilibrium between the biomolecules, which contributes to mitochondrial dysfunction. Here, we investigate the effect of the ionic environment on the interactions of Aβ (Aβ_1–40, Aβ_1–42) with cypD and 17β-HSD10 using a surface plasmon resonance (SPR) biosensor. We show that changes in concentrations of K⁺ and Mg²⁺ significantly affect the interactions and may increase the binding efficiency between the biomolecules by up to 35% and 65% for the interactions with Aβ_1–40 and Aβ_1–42, respectively, in comparison with the physiological state. We also demonstrate that while the binding of Aβ_1–40 to cypD and 17β-HSD10 takes place preferentially around the physiological concentrations of ions, decreased concentrations of K⁺ and increased concentrations of Mg²⁺ promote the interaction of both mitochondrial proteins with Aβ_1–42. These results suggest that the ionic environment represents an important factor that should be considered in the investigation of biomolecular interactions taking place in the mitochondrial matrix under physiological as well as AD-associated conditions. Full article

(This article belongs to the Special Issue Amyloid-β: Structure, Function, and Pathophysiological Significance in Neurodegenerative Diseases 2.0)

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Review

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14 pages, 2548 KiB

Open AccessReview

Interactions of Amyloid-β with Membrane Proteins

by Benita Wiatrak, Janusz Piasny, Amadeusz Kuźniarski and Kazimierz Gąsiorowski

Int. J. Mol. Sci. 2021, 22(11), 6075; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22116075 - 04 Jun 2021

Cited by 17 | Viewed by 2927

Abstract

In developing and developed countries, an increasing elderly population is observed. This affects the growing percentage of people struggling with neurodegenerative diseases, including Alzheimer’s disease. Nevertheless, the pathomechanism of this disease is still unknown. This contributes to problems with early diagnosis of the disease as well as with treatment. One of the most popular hypotheses of Alzheimer’s disease is related to the pathological deposition of amyloid-β (Aβ) in the brain of ill people. In this paper, we discuss issues related to Aβ and its relationship in the development of Alzheimer’s disease. The structure of Aβ and its interaction with the cell membrane are discussed. Not only do the extracellular plaques affect nerve cells, but other forms of this peptide as well. Full article

(This article belongs to the Special Issue Amyloid-β: Structure, Function, and Pathophysiological Significance in Neurodegenerative Diseases 2.0)

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15 pages, 673 KiB

Open AccessReview

Current Management and Therapeutic Strategies for Cerebral Amyloid Angiopathy

by Yasuteru Inoue, Yukio Ando, Yohei Misumi and Mitsuharu Ueda

Int. J. Mol. Sci. 2021, 22(8), 3869; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22083869 - 08 Apr 2021

Cited by 11 | Viewed by 4893

Abstract

Cerebral amyloid angiopathy (CAA) is characterized by accumulation of amyloid β (Aβ) in walls of leptomeningeal vessels and cortical capillaries in the brain. The loss of integrity of these vessels caused by cerebrovascular Aβ deposits results in fragile vessels and lobar intracerebral hemorrhages. CAA also manifests with progressive cognitive impairment or transient focal neurological symptoms. Although development of therapeutics for CAA is urgently needed, the pathogenesis of CAA remains to be fully elucidated. In this review, we summarize the epidemiology, pathology, clinical and radiological features, and perspectives for future research directions in CAA therapeutics. Recent advances in mass spectrometric methodology combined with vascular isolation techniques have aided understanding of the cerebrovascular proteome. In this paper, we describe several potential key CAA-associated molecules that have been identified by proteomic analyses (apolipoprotein E, clusterin, SRPX1 (sushi repeat-containing protein X-linked 1), TIMP3 (tissue inhibitor of metalloproteinases 3), and HTRA1 (HtrA serine peptidase 1)), and their pivotal roles in Aβ cytotoxicity, Aβ fibril formation, and vessel wall remodeling. Understanding the interactions between cerebrovascular Aβ deposits and molecules that accumulate with Aβ may lead to discovery of effective CAA therapeutics and to the identification of biomarkers for early diagnosis. Full article

(This article belongs to the Special Issue Amyloid-β: Structure, Function, and Pathophysiological Significance in Neurodegenerative Diseases 2.0)

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25 pages, 3288 KiB

Open AccessReview

Role of Retinal Amyloid-β in Neurodegenerative Diseases: Overlapping Mechanisms and Emerging Clinical Applications

by Liang Wang and Xiaobo Mao

Int. J. Mol. Sci. 2021, 22(5), 2360; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052360 - 26 Feb 2021

Cited by 28 | Viewed by 4872

Abstract

Amyloid-β (Aβ) accumulations have been identified in the retina for neurodegeneration-associated disorders like Alzheimer’s disease (AD), glaucoma, and age-related macular degeneration (AMD). Elevated retinal Aβ levels were associated with progressive retinal neurodegeneration, elevated cerebral Aβ accumulation, and increased disease severity with a decline in cognition and vision. Retinal Aβ accumulation and its pathological effects were demonstrated to occur prior to irreversible neurodegeneration, which highlights its potential in early disease detection and intervention. Using the retina as a model of the brain, recent studies have focused on characterizing retinal Aβ to determine its applicability for population-based screening of AD, which warrants a further understanding of how Aβ manifests between these disorders. While current treatments directly targeting Aβ accumulations have had limited results, continued exploration of Aβ-associated pathological pathways may yield new therapeutic targets for preserving cognition and vision. Here, we provide a review on the role of retinal Aβ manifestations in these distinct neurodegeneration-associated disorders. We also discuss the recent applications of retinal Aβ for AD screening and current clinical trial outcomes for Aβ-associated treatment approaches. Lastly, we explore potential future therapeutic targets based on overlapping mechanisms of pathophysiology in AD, glaucoma, and AMD. Full article

(This article belongs to the Special Issue Amyloid-β: Structure, Function, and Pathophysiological Significance in Neurodegenerative Diseases 2.0)

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17 pages, 2143 KiB

Open AccessReview

Natural Products Targeting Amyloid Beta in Alzheimer’s Disease

by Joo-Hee Lee, Na-Hyun Ahn, Su-Bin Choi, Youngeun Kwon and Seung-Hoon Yang

Int. J. Mol. Sci. 2021, 22(5), 2341; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052341 - 26 Feb 2021

Cited by 21 | Viewed by 6603

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by severe brain damage and dementia. There are currently few therapeutics to treat this disease, and they can only temporarily alleviate some of the symptoms. The pathogenesis of AD is mainly preceded by accumulation of abnormal amyloid beta (Aβ) aggregates, which are toxic to neurons. Therefore, modulation of the formation of these abnormal aggregates is strongly suggested as the most effective approach to treat AD. In particular, numerous studies on natural products associated with AD, aiming to downregulate Aβ peptides and suppress the formation of abnormal Aβ aggregates, thus reducing neural cell death, are being conducted. Generation of Aβ peptides can be prevented by targeting the secretases involved in Aβ-peptide formation (secretase-dependent). Additionally, blocking the intra- and intermolecular interactions of Aβ peptides can induce conformational changes in abnormal Aβ aggregates, whereby the toxicity can be ameliorated (structure-dependent). In this review, AD-associated natural products which can reduce the accumulation of Aβ peptides via secretase- or structure-dependent pathways, and the current clinical trial states of these products are discussed. Full article

(This article belongs to the Special Issue Amyloid-β: Structure, Function, and Pathophysiological Significance in Neurodegenerative Diseases 2.0)

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14 pages, 5692 KiB

Open AccessReview

Promotion and Inhibition of Amyloid-β Peptide Aggregation: Molecular Dynamics Studies

by Satoru G. Itoh and Hisashi Okumura

Int. J. Mol. Sci. 2021, 22(4), 1859; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041859 - 13 Feb 2021

Cited by 13 | Viewed by 4015

Abstract

Aggregates of amyloid-β (Aβ) peptides are known to be related to Alzheimer’s disease. Their aggregation is enhanced at hydrophilic–hydrophobic interfaces, such as a cell membrane surface and air-water interface, and is inhibited by polyphenols, such as myricetin and rosmarinic acid. We review molecular dynamics (MD) simulation approaches of a full-length Aβ peptide, Aβ40, and Aβ(16–22) fragments in these environments. Since these peptides have both hydrophilic and hydrophobic amino acid residues, they tend to exist at the interfaces. The high concentration of the peptides accelerates the aggregation there. In addition, Aβ40 forms a β-hairpin structure, and this structure accelerates the aggregation. We also describe the inhibition mechanism of the Aβ(16–22) aggregation by polyphenols. The aggregation of Aβ(16–22) fragments is caused mainly by the electrostatic attraction between charged amino acid residues known as Lys16 and Glu22. Since polyphenols form hydrogen bonds between their hydroxy and carboxyl groups and these charged amino acid residues, they inhibit the aggregation. Full article

(This article belongs to the Special Issue Amyloid-β: Structure, Function, and Pathophysiological Significance in Neurodegenerative Diseases 2.0)

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Other

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11 pages, 1702 KiB

Open AccessOpinion

Using Optogenetics to Model Cellular Effects of Alzheimer’s Disease

by Prabhat Tiwari and Nicholas S. Tolwinski

Int. J. Mol. Sci. 2023, 24(5), 4300; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24054300 - 21 Feb 2023

Cited by 1 | Viewed by 2100

Abstract

Across the world a dementia case is diagnosed every three seconds. Alzheimer’s disease (AD) causes 50–60% of these cases. The most prominent theory for AD correlates the deposition of amyloid beta (Aβ) with the onset of dementia. Whether Aβ is causative remains unclear due to findings such as the recently approved drug Aducanumab showing effective clearance of Aβ, but not improving cognition. New approaches for understanding Aβ function, are therefore necessary. Here we discuss the application of optogenetic techniques to gain insight into AD. Optogenetics, or genetically encoded, light-dependent on/off switches, provides precise spatiotemporal control to regulate cellular dynamics. This precise control over protein expression and oligomerization or aggregation could provide a better understanding of the etiology of AD. Full article

(This article belongs to the Special Issue Amyloid-β: Structure, Function, and Pathophysiological Significance in Neurodegenerative Diseases 2.0)

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