International Journal of Molecular Sciences

Editorial

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3 pages, 182 KiB

Open AccessEditorial

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

by Satoshi Saito, Kenjiro Ono and Masashi Tanaka

Int. J. Mol. Sci. 2022, 23(18), 10275; https://doi.org/10.3390/ijms231810275 - 7 Sep 2022

Viewed by 1495

Abstract

The rate of dementia continues to increase worldwide; however, there currently exist no therapeutic strategies for this condition [...] Full article

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

Research

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19 pages, 5919 KiB

Open AccessArticle

Seeding and Growth of β-Amyloid Aggregates upon Interaction with Neuronal Cell Membranes

by Álvaro Ruiz-Arias, Jose M. Paredes, Chiara Di Biase, Juan M. Cuerva, María D. Giron, Rafael Salto, Juan A. González-Vera and Angel Orte

Int. J. Mol. Sci. 2020, 21(14), 5035; https://doi.org/10.3390/ijms21145035 - 16 Jul 2020

Cited by 9 | Viewed by 4293

Abstract

In recent years, the prevalence of amyloid neurodegenerative diseases such as Alzheimer’s disease (AD) has significantly increased in developed countries due to increased life expectancy. This amyloid disease is characterized by the presence of accumulations and deposits of β-amyloid peptide (Aβ) in neuronal [...] Read more.

In recent years, the prevalence of amyloid neurodegenerative diseases such as Alzheimer’s disease (AD) has significantly increased in developed countries due to increased life expectancy. This amyloid disease is characterized by the presence of accumulations and deposits of β-amyloid peptide (Aβ) in neuronal tissue, leading to the formation of oligomers, fibers, and plaques. First, oligomeric intermediates that arise during the aggregation process are currently thought to be primarily responsible for cytotoxicity in cells. This work aims to provide further insights into the mechanisms of cytotoxicity by studying the interaction of Aβ aggregates with Neuro-2a (N2a) neuronal cells and the effects caused by this interaction. For this purpose, we have exploited the advantages of advanced, multidimensional fluorescence microscopy techniques to determine whether different types of Aβ are involved in higher rates of cellular toxicity, and we measured the cellular stress caused by such aggregates by using a fluorogenic intracellular biothiol sensor. Stress provoked by the peptide is evident by N2a cells generating high levels of biothiols as a defense mechanism. In our study, we demonstrate that Aβ aggregates act as seeds for aggregate growth upon interacting with the cellular membrane, which results in cell permeability and damage and induces lysis. In parallel, these damaged cells undergo a significant increase in intracellular biothiol levels. Full article

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

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18 pages, 3594 KiB

Open AccessArticle

Conformational Characterization of Native and L17A/F19A-Substituted Dutch-Type β-Amyloid Peptides

by Kai-Cyuan He, Yi-Ru Chen, Chu-Ting Liang, Shi-Jie Huang, Chung-Ying Tzeng, Chi-Fon Chang, Shing-Jong Huang, Hsien-Bin Huang and Ta-Hsien Lin

Int. J. Mol. Sci. 2020, 21(7), 2571; https://doi.org/10.3390/ijms21072571 - 7 Apr 2020

Cited by 6 | Viewed by 3069

Abstract

Some mutations which occur in the α/β-discordant region (resides 15 to 23) of β-amyloid peptide (Aβ) lead to familial Alzheimer’s disease (FAD). In vitro studies have shown that these genetic mutations could accelerate Aβ aggregation. We recently showed that mutations in this region [...] Read more.

Some mutations which occur in the α/β-discordant region (resides 15 to 23) of β-amyloid peptide (Aβ) lead to familial Alzheimer’s disease (FAD). In vitro studies have shown that these genetic mutations could accelerate Aβ aggregation. We recently showed that mutations in this region could alter the structural propensity, resulting in a different aggregative propensity of Aβ. Whether these genetic mutations display similar effects remains largely unknown. Here, we characterized the structural propensity and aggregation kinetics of Dutch-type Aβ₄₀ (Aβ₄₀(E22Q)) and its L17A/F19A-substituted mutant (Aβ₄₀(L17A/F19A/E22Q)) using circular dichroism spectroscopy, nuclear magnetic spectroscopy, and thioflavin T fluorescence assay. In comparison with wild-type Aβ₄₀, we found that Dutch-type mutation, unlike Artic-type mutation (E22G), does not reduce the α-helical propensity of the α/β-discordant region in sodium dodecyl sulfate micellar solution. Moreover, we found that Aβ₄₀(L17A/F19A/E22Q) displays a higher α-helical propensity of the α/β-discordant region and a slower aggregation rate than Aβ₄₀(E22Q), suggesting that the inhibition of aggregation might be via increasing the α-helical propensity of the α/β-discordant region, similar to that observed in wild-type and Artic-type Aβ₄₀. Taken together, Dutch-type and Artic-type mutations adopt different mechanisms to promote Aβ aggregation, however, the L17A/F19A mutation could increase the α-helical propensities of both Dutch-type and Artic-type Aβ₄₀ and inhibit their aggregation. Full article

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

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15 pages, 4716 KiB

Open AccessArticle

Low-Dose Phosphodiesterase III Inhibitor Reduces the Vascular Amyloid Burden in Amyloid-β Protein Precursor Transgenic Mice

by Yusuke Yakushiji, Kazuhiro Kawamoto, Kazuyoshi Uchihashi, Masafumi Ihara, Shigehisa Aoki, Yukiko Nagaishi, Kohei Suzuyama, Yumiko Tsugitomi and Hideo Hara

Int. J. Mol. Sci. 2020, 21(7), 2295; https://doi.org/10.3390/ijms21072295 - 26 Mar 2020

Cited by 7 | Viewed by 2823

Abstract

A previous study reported that relatively high-dose cilostazol (0.3%) promoted the drainage of cerebrovascular amyloid-β (Aβ) protein in Aβ Precursor Protein (APP) transgenic mice overexpressing vasculotropic Aβ. We investigated whether lower-dose cilostazol can decrease micro-hemorrhages and Aβ deposition in the brain using APP [...] Read more.

A previous study reported that relatively high-dose cilostazol (0.3%) promoted the drainage of cerebrovascular amyloid-β (Aβ) protein in Aβ Precursor Protein (APP) transgenic mice overexpressing vasculotropic Aβ. We investigated whether lower-dose cilostazol can decrease micro-hemorrhages and Aβ deposition in the brain using APP transgenic mice. At baseline, 14-month-old female Tg2576 mice were randomly assigned to a control group (vehicle), aspirin group (0.01% aspirin), or cilostazol group (0.01% cilostazol). The severity of cerebral micro-hemorrhages (i.e., number), area of senile plaque, and severity of vascular amyloid burden (quantified with cerebral amyloid angiopathy (CAA) score (=number of Aβ-positive vessels × severity of amyloid burden of Aβ-positive vessels) were evaluated in the brain of mice aged 15 and 21–23 months. At 15 months, no differences were shown in each pathological change among the three groups. At 21–23 months, there were no differences in the severity of cerebral micro-hemorrhages or area of senile plaque among the three groups. However, the CAA score was significantly lower in the cilostazol compared to the control group (p = 0.046, Mann–Whitney U test), although no difference was seen between the control and aspirin group. Our study showed that lower-dose cilostazol could reduce the vascular amyloid burden without increasing cerebral micro-hemorrhages in APP transgenic mice. Full article

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

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13 pages, 2677 KiB

Open AccessArticle

Evaluation of Toxic Amyloid β42 Oligomers in Rat Primary Cerebral Cortex Cells and Human iPS-derived Neurons Treated with 10-Me-Aplog-1, a New PKC Activator

by Kazuma Murakami, Mayuko Yoshimura, Shota Nakagawa, Toshiaki Kume, Takayuki Kondo, Haruhisa Inoue and Kazuhiro Irie

Int. J. Mol. Sci. 2020, 21(4), 1179; https://doi.org/10.3390/ijms21041179 - 11 Feb 2020

Cited by 6 | Viewed by 3921

Abstract

Amyloid β42 (Aβ42), a causative agent of Alzheimer’s disease (AD), is derived extracellularly from Aβ precursor protein (APP) following the latter’s cleavage by β-secretase, but not α-secretase. Protein kinase Cα (PKCα) activation is known to increase α [...] Read more.

Amyloid β42 (Aβ42), a causative agent of Alzheimer’s disease (AD), is derived extracellularly from Aβ precursor protein (APP) following the latter’s cleavage by β-secretase, but not α-secretase. Protein kinase Cα (PKCα) activation is known to increase α-secretase activity, thereby suppressing Aβ production. Since Aβ42 oligomer formation causes potent neurotoxicity, APP modulation by PKC ligands is a promising strategy for AD treatment. Although bryostatin-1 (bryo-1) is a leading compound for this strategy, its limited natural availability and the difficulty of its total synthesis impedes further research. To address this limitation, Irie and colleagues have developed a new PKC activator with few side effects, 10-Me-Aplog-1, (1), which decreased Aβ42 in the conditioned medium of rat primary cerebral cortex cells. These results are associated with increased α-secretase but not PKCε-dependent Aβ-degrading enzyme. The amount of neuronal embryonic lethal abnormal vision (nELAV), a known β-secretase stabilizer, was reduced by treatment with 1. Notably, 1 prevented the formation of intracellular toxic oligomers. Furthermore, 1 suppressed toxic oligomerization within human iPS-derived neurons such as bryo-1. Given that 1 was not neurotoxic toward either cell line, these findings suggest that 1 is a potential drug lead for AD therapy. Full article

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

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18 pages, 5149 KiB

Open AccessArticle

Interaction of Aβ42 with Membranes Triggers the Self-Assembly into Oligomers

by Siddhartha Banerjee, Mohtadin Hashemi, Karen Zagorski and Yuri L. Lyubchenko

Int. J. Mol. Sci. 2020, 21(3), 1129; https://doi.org/10.3390/ijms21031129 - 8 Feb 2020

Cited by 31 | Viewed by 4195

Abstract

The self-assembly of amyloid β (Aβ) proteins into oligomers is the major pathogenic event leading to Alzheimer’s disease (AD). Typical in vitro experiments require high protein concentrations, whereas the physiological concentration of Aβ is in the picomolar to low nanomolar range. This complicates [...] Read more.

The self-assembly of amyloid β (Aβ) proteins into oligomers is the major pathogenic event leading to Alzheimer’s disease (AD). Typical in vitro experiments require high protein concentrations, whereas the physiological concentration of Aβ is in the picomolar to low nanomolar range. This complicates the translation of results obtained in vitro to understanding the aggregation process in vivo. Here, we demonstrate that Aβ42 self-assembles into aggregates on membrane bilayers at low nanomolar concentrations - a pathway in which the membrane plays the role of a catalyst. Additionally, physiological ionic conditions (150 mM NaCl) significantly enhance on-membrane aggregation, leading to the rapid formation of oligomers. The self-assembly process is reversible, so assembled aggregates can dissociate from the membrane surface into the bulk solution to further participate in the aggregation process. Molecular dynamics simulations demonstrate that the transient membrane-Aβ interaction dramatically changes the protein conformation, facilitating the assembly of dimers. The results indicate peptide–membrane interaction is the critical step towards oligomer formation at physiologically low protein concentrations. Full article

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

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25 pages, 6930 KiB

Open AccessArticle

Patterns of Expression of Purinergic Receptor P2RY12, a Putative Marker for Non-Activated Microglia, in Aged and Alzheimer’s Disease Brains

by Douglas G. Walker, Tiffany M. Tang, Anarmaa Mendsaikhan, Ikuo Tooyama, Geidy E. Serrano, Lucia I. Sue, Thomas G. Beach and Lih-Fen Lue

Int. J. Mol. Sci. 2020, 21(2), 678; https://doi.org/10.3390/ijms21020678 - 20 Jan 2020

Cited by 83 | Viewed by 9246

Abstract

Neuroinflammation is considered a key pathological process in neurodegenerative diseases of aging, including Alzheimer’s disease (AD). Many studies have defined phenotypes of reactive microglia, the brain-resident macrophages, with different antigenic markers to identify those potentially causing inflammatory damage. We took an alternative approach [...] Read more.

Neuroinflammation is considered a key pathological process in neurodegenerative diseases of aging, including Alzheimer’s disease (AD). Many studies have defined phenotypes of reactive microglia, the brain-resident macrophages, with different antigenic markers to identify those potentially causing inflammatory damage. We took an alternative approach with the goal of characterizing the distribution of purinergic receptor P2RY12-positive microglia, a marker previously defined as identifying homeostatic or non-activated microglia. We examined the expression of P2RY12 by dual-color light and fluorescence immunohistochemistry using sections of middle temporal gyrus from AD, high plaque and low plaque non-demented cases in relation to amyloid beta (Aβ) plaques and phosphorylated tau, markers of pathology, and HLA-DR, IBA-1, CD68, and progranulin, microglial phenotype markers. In low plaque cases, P2RY12-positive microglia mostly had non-activated morphologies, while the morphologies of P2RY12-positive microglia in AD brains were highly variable, suggesting its expression could encompass a wider range of phenotypes than originally hypothesized. P2RY12 expression by microglia differed depending on the types of plaques or tangles they were associated with. Areas of inflammation characterized by lack of P2RY12-positive microglia around mature plaques could be observed, but many diffuse plaques showed colocalization with P2RY12-positive microglia. Based on these results, P2RY12 expression by microglia should not be considered solely a marker of resting microglia as P2RY12 immunoreactivity was identifying microglia positive for CD68, progranulin and to a limited extent HLA-DR, markers of activation. Full article

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

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Review

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19 pages, 1812 KiB

Open AccessReview

The Use of Antimicrobial and Antiviral Drugs in Alzheimer’s Disease

by Umar H. Iqbal, Emma Zeng and Giulio M. Pasinetti

Int. J. Mol. Sci. 2020, 21(14), 4920; https://doi.org/10.3390/ijms21144920 - 12 Jul 2020

Cited by 34 | Viewed by 5419

Abstract

The aggregation and accumulation of amyloid-β plaques and tau proteins in the brain have been central characteristics in the pathophysiology of Alzheimer’s disease (AD), making them the focus of most of the research exploring potential therapeutics for this neurodegenerative disease. With success in [...] Read more.

The aggregation and accumulation of amyloid-β plaques and tau proteins in the brain have been central characteristics in the pathophysiology of Alzheimer’s disease (AD), making them the focus of most of the research exploring potential therapeutics for this neurodegenerative disease. With success in interventions aimed at depleting amyloid-β peptides being limited at best, a greater understanding of the physiological role of amyloid-β peptides is needed. The development of amyloid-β plaques has been determined to occur 10–20 years prior to AD symptom manifestation, hence earlier interventions might be necessary to address presymptomatic AD. Furthermore, recent studies have suggested that amyloid-β peptides may play a role in innate immunity as an antimicrobial peptide. These findings, coupled with the evidence of pathogens such as viruses and bacteria in AD brains, suggests that the buildup of amyloid-β plaques could be a response to the presence of viruses and bacteria. This has led to the foundation of the antimicrobial hypothesis for AD. The present review will highlight the current understanding of amyloid-β, and the role of bacteria and viruses in AD, and will also explore the therapeutic potential of antimicrobial and antiviral drugs in Alzheimer’s disease. Full article

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

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14 pages, 986 KiB

Open AccessReview

Natural Medicines and Their Underlying Mechanisms of Prevention and Recovery from Amyloid Β-Induced Axonal Degeneration in Alzheimer’s Disease

by Tomoharu Kuboyama, Ximeng Yang and Chihiro Tohda

Int. J. Mol. Sci. 2020, 21(13), 4665; https://doi.org/10.3390/ijms21134665 - 30 Jun 2020

Cited by 6 | Viewed by 3357

Abstract

In Alzheimer’s disease (AD), amyloid β (Aβ) induces axonal degeneration, neuronal network disruption, and memory impairment. Although many candidate drugs to reduce Aβ have been clinically investigated, they failed to recover the memory function in AD patients. Reportedly, Aβ deposition occurred before the [...] Read more.

In Alzheimer’s disease (AD), amyloid β (Aβ) induces axonal degeneration, neuronal network disruption, and memory impairment. Although many candidate drugs to reduce Aβ have been clinically investigated, they failed to recover the memory function in AD patients. Reportedly, Aβ deposition occurred before the onset of AD. Once neuronal networks were disrupted by Aβ, they could hardly be recovered. Therefore, we speculated that only removal of Aβ was not enough for AD therapy, and prevention and recovery from neuronal network disruption were also needed. This review describes the challenges related to the condition of axons for AD therapy. We established novel in vitro models of Aβ-induced axonal degeneration. Using these models, we found that several traditional medicines and their constituents prevented or helped recover from Aβ-induced axonal degeneration. These drugs also prevented or helped recover from memory impairment in in vivo models of AD. One of these drugs ameliorated memory decline in AD patients in a clinical study. These results indicate that prevention and recovery from axonal degeneration are possible strategies for AD therapy. Full article

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

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30 pages, 14411 KiB

Open AccessReview

High-Speed Atomic Force Microscopy Reveals the Structural Dynamics of the Amyloid-β and Amylin Aggregation Pathways

by Takahiro Watanabe-Nakayama, Bikash R. Sahoo, Ayyalusamy Ramamoorthy and Kenjiro Ono

Int. J. Mol. Sci. 2020, 21(12), 4287; https://doi.org/10.3390/ijms21124287 - 16 Jun 2020

Cited by 27 | Viewed by 5812

Abstract

Individual Alzheimer’s disease (AD) patients have been shown to have structurally distinct amyloid-β (Aβ) aggregates, including fibrils, in their brain. These findings suggest the possibility of a relationship between AD progression and Aβ fibril structures. Thus, the characterization of the structural dynamics of [...] Read more.

Individual Alzheimer’s disease (AD) patients have been shown to have structurally distinct amyloid-β (Aβ) aggregates, including fibrils, in their brain. These findings suggest the possibility of a relationship between AD progression and Aβ fibril structures. Thus, the characterization of the structural dynamics of Aβ could aid the development of novel therapeutic strategies and diagnosis. Protein structure and dynamics have typically been studied separately. Most of the commonly used biophysical approaches are limited in providing substantial details regarding the combination of both structure and dynamics. On the other hand, high-speed atomic force microscopy (HS-AFM), which simultaneously visualizes an individual protein structure and its dynamics in liquid in real time, can uniquely link the structure and the kinetic details, and it can also unveil novel insights. Although amyloidogenic proteins generate heterogeneously aggregated species, including transient unstable states during the aggregation process, HS-AFM elucidated the structural dynamics of individual aggregates in real time in liquid without purification and isolation. Here, we review and discuss the HS-AFM imaging of amyloid aggregation and strategies to optimize the experiments showing findings from Aβ and amylin, which is associated with type II diabetes, shares some common biological features with Aβ, and is reported to be involved in AD. Full article

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

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19 pages, 1465 KiB

Open AccessReview

Polyphenols with Anti-Amyloid β Aggregation Show Potential Risk of Toxicity Via Pro-Oxidant Properties

by Hatasu Kobayashi, Mariko Murata, Shosuke Kawanishi and Shinji Oikawa

Int. J. Mol. Sci. 2020, 21(10), 3561; https://doi.org/10.3390/ijms21103561 - 18 May 2020

Cited by 33 | Viewed by 4321

Abstract

Alzheimer’s disease (AD) is the most common form of dementia among older people. Amyloid β (Aβ) aggregation has been the focus for a therapeutic target for the treatment of AD. Naturally occurring polyphenols have an inhibitory effect on Aβ aggregation and have attracted [...] Read more.

Alzheimer’s disease (AD) is the most common form of dementia among older people. Amyloid β (Aβ) aggregation has been the focus for a therapeutic target for the treatment of AD. Naturally occurring polyphenols have an inhibitory effect on Aβ aggregation and have attracted a lot of attention for the development of treatment strategies which could mitigate the symptoms of AD. However, considerable evidence has shown that the pro-oxidant mechanisms of polyphenols could have a deleterious effect. Our group has established an assay system to evaluate the pro-oxidant characteristics of chemical compounds, based on their reactivity with DNA. In this review, we have summarized the anti-Aβ aggregation and pro-oxidant properties of polyphenols. These findings could contribute to understanding the mechanism underlying the potential risk of polyphenols. We would like to emphasize the importance of assessing the pro-oxidant properties of polyphenols from a safety point of view. Full article

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

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18 pages, 1202 KiB

Open AccessReview

Prevention of Cognitive Decline in Alzheimer’s Disease by Novel Antioxidative Supplements

by Koh Tadokoro, Yasuyuki Ohta, Haruhiko Inufusa, Alan Foo Nyuk Loon and Koji Abe

Int. J. Mol. Sci. 2020, 21(6), 1974; https://doi.org/10.3390/ijms21061974 - 13 Mar 2020

Cited by 41 | Viewed by 7799

Abstract

Oxidative stress plays a crucial role in Alzheimer’s disease (AD) from its prodromal stage of mild cognitive impairment. There is an interplay between oxidative stress and the amyloid β (Aβ) cascade via various mechanisms including mitochondrial dysfunction, lipid peroxidation, protein oxidation, glycoxidation, deoxyribonucleotide [...] Read more.

Oxidative stress plays a crucial role in Alzheimer’s disease (AD) from its prodromal stage of mild cognitive impairment. There is an interplay between oxidative stress and the amyloid β (Aβ) cascade via various mechanisms including mitochondrial dysfunction, lipid peroxidation, protein oxidation, glycoxidation, deoxyribonucleotide acid damage, altered antioxidant defense, impaired amyloid clearance, inflammation and chronic cerebral hypoperfusion. Based on findings that indicate that oxidative stress plays a major role in AD, oxidative stress has been considered as a therapeutic target of AD. In spite of favorable preclinical study outcomes, previous antioxidative components, including a single antioxidative supplement such as vitamin C, vitamin E or their mixtures, did not clearly show any therapeutic effect on cognitive decline in AD. However, novel antioxidative supplements can be beneficial for AD patients. In this review, we summarize the interplay between oxidative stress and the Aβ cascade, and introduce novel antioxidative supplements expected to prevent cognitive decline in AD. Full article

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

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19 pages, 2961 KiB

Open AccessReview

APP Osaka Mutation in Familial Alzheimer’s Disease—Its Discovery, Phenotypes, and Mechanism of Recessive Inheritance

by Takami Tomiyama and Hiroyuki Shimada

Int. J. Mol. Sci. 2020, 21(4), 1413; https://doi.org/10.3390/ijms21041413 - 19 Feb 2020

Cited by 36 | Viewed by 6622

Abstract

Alzheimer’s disease is believed to begin with synaptic dysfunction caused by soluble Aβ oligomers. When this oligomer hypothesis was proposed in 2002, there was no direct evidence that Aβ oligomers actually disrupt synaptic function to cause cognitive impairment in humans. In patient brains, [...] Read more.

Alzheimer’s disease is believed to begin with synaptic dysfunction caused by soluble Aβ oligomers. When this oligomer hypothesis was proposed in 2002, there was no direct evidence that Aβ oligomers actually disrupt synaptic function to cause cognitive impairment in humans. In patient brains, both soluble and insoluble Aβ species always coexist, and therefore it is difficult to determine which pathologies are caused by Aβ oligomers and which are caused by amyloid fibrils. Thus, no validity of the oligomer hypothesis was available until the Osaka mutation was discovered. This mutation, which was found in a Japanese pedigree of familial Alzheimer’s disease, is the deletion of codon 693 of APP gene, resulting in mutant Aβ lacking the 22nd glutamate. Only homozygous carriers suffer from dementia. In vitro studies revealed that this mutation has a very unique character that accelerates Aβ oligomerization but does not form amyloid fibrils. Model mice expressing this mutation demonstrated that all pathologies of Alzheimer’s disease can be induced by Aβ oligomers alone. In this review, we describe the story behind the discovery of the Osaka mutation, summarize the mutant’s phenotypes, and propose a mechanism of its recessive inheritance. Full article

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

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13 pages, 941 KiB

Open AccessReview

Protofibrils of Amyloid-β are Important Targets of a Disease-Modifying Approach for Alzheimer’s Disease

by Kenjiro Ono and Mayumi Tsuji

Int. J. Mol. Sci. 2020, 21(3), 952; https://doi.org/10.3390/ijms21030952 - 31 Jan 2020

Cited by 47 | Viewed by 7413

Abstract

Worldwide, Alzheimer’s disease (AD) is the most common age-related neurodegenerative disease and is characterized by unique pathological hallmarks in the brain, including plaques composed of amyloid β-protein (Aβ) and neurofibrillary tangles of tau protein. Genetic studies, biochemical data, and animal models have suggested [...] Read more.

Worldwide, Alzheimer’s disease (AD) is the most common age-related neurodegenerative disease and is characterized by unique pathological hallmarks in the brain, including plaques composed of amyloid β-protein (Aβ) and neurofibrillary tangles of tau protein. Genetic studies, biochemical data, and animal models have suggested that Aβ is responsible for the pathogenesis of AD (i.e., the amyloid hypothesis). Indeed, Aβ molecules tend to aggregate, forming oligomers, protofibrils, and mature fibrils. However, while these Aβ species form amyloid plaques of the type implicated in AD neurodegeneration, recent clinical trials designed to reduce the production of Aβ and/or the plaque burden have not demonstrated clinical efficacy. In addition, recent studies using synthetic Aβ peptides, cell culture models, Arctic transgenic mice, and human samples of AD brain tissues have suggested that the pre-fibrillar forms of Aβ, particularly Aβ protofibrils, may be the most critical species, compared with extracellular fibrillar forms. We recently reported that protofibrils of Aβ_1-42 disturbed membrane integrity by inducing reactive oxygen species generation and lipid peroxidation, resulting in decreased membrane fluidity, intracellular calcium dysregulation, depolarization, and synaptic toxicity. Therefore, the therapeutic reduction of protofibrils may prevent the progression of AD by ameliorating neuronal damage and cognitive dysfunction through multiple mechanisms. Full article

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

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11 pages, 2788 KiB

Open AccessCase Report

Heavy Tau Burden with Subtle Amyloid β Accumulation in the Cerebral Cortex and Cerebellum in a Case of Familial Alzheimer’s Disease with APP Osaka Mutation

by Hiroyuki Shimada, Shinobu Minatani, Jun Takeuchi, Akitoshi Takeda, Joji Kawabe, Yasuhiro Wada, Aya Mawatari, Yasuyoshi Watanabe, Hitoshi Shimada, Makoto Higuchi, Tetsuya Suhara, Takami Tomiyama and Yoshiaki Itoh

Int. J. Mol. Sci. 2020, 21(12), 4443; https://doi.org/10.3390/ijms21124443 - 22 Jun 2020

Cited by 10 | Viewed by 3326

Abstract

We previously identified a novel mutation in amyloid precursor protein from a Japanese pedigree of familial Alzheimer’s disease, FAD (Osaka). Our previous positron emission tomography (PET) study revealed that amyloid β (Aβ) accumulation was negligible in two sister cases of this pedigree, indicating [...] Read more.

We previously identified a novel mutation in amyloid precursor protein from a Japanese pedigree of familial Alzheimer’s disease, FAD (Osaka). Our previous positron emission tomography (PET) study revealed that amyloid β (Aβ) accumulation was negligible in two sister cases of this pedigree, indicating a possibility that this mutation induces dementia without forming senile plaques. To further explore the relationship between Aβ, tau and neurodegeneration, we performed tau and Aβ PET imaging in the proband of FAD (Osaka) and in patients with sporadic Alzheimer’s disease (SAD) and healthy controls (HCs). The FAD (Osaka) patient showed higher uptake of tau PET tracer in the frontal, lateral temporal, and parietal cortices, posterior cingulate gyrus and precuneus than the HCs (>2.5 SD) and in the lateral temporal and parietal cortices than the SAD patients (>2 SD). Most noticeably, heavy tau tracer accumulation in the cerebellum was found only in the FAD (Osaka) patient. Scatter plot analysis of the two tracers revealed that FAD (Osaka) exhibits a distinguishing pattern with a heavy tau burden and subtle Aβ accumulation in the cerebral cortex and cerebellum. These observations support our hypothesis that Aβ can induce tau accumulation and neuronal degeneration without forming senile plaques. Full article

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

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6 pages, 210 KiB

Open AccessCommentary

What Are the Molecular Mechanisms by Which Functional Bacterial Amyloids Influence Amyloid Beta Deposition and Neuroinflammation in Neurodegenerative Disorders?

by Robert P. Friedland, Joseph D. McMillan and Zimple Kurlawala

Int. J. Mol. Sci. 2020, 21(5), 1652; https://doi.org/10.3390/ijms21051652 - 28 Feb 2020

Cited by 39 | Viewed by 4290

Abstract

Despite the enormous literature documenting the importance of amyloid beta (Ab) protein in Alzheimer's disease, we do not know how Ab aggregation is initiated and why it has its unique distribution in the brain. In vivo and in vitro evidence has been developed [...] Read more.

Despite the enormous literature documenting the importance of amyloid beta (Ab) protein in Alzheimer's disease, we do not know how Ab aggregation is initiated and why it has its unique distribution in the brain. In vivo and in vitro evidence has been developed to suggest that functional microbial amyloid proteins produced in the gut may cross-seed Ab aggregation and prime the innate immune system to have an enhanced and pathogenic response to neuronal amyloids. In this commentary, we summarize the molecular mechanisms by which the microbiota may initiate and sustain the pathogenic processes of neurodegeneration in aging. Full article

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

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