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
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.
Lewy body diseases (LBD) are pathologically defined as the accumulation of Lewy bodies composed of an aggregation of α-synuclein (αSyn). In LBD, not only the sole aggregation of αSyn but also the ...co-aggregation of amyloidogenic proteins, such as amyloid-β (Aβ) and tau, has been reported. In this review, the pathophysiology of co-aggregation of αSyn, Aβ, and tau protein and the advancement in imaging and fluid biomarkers that can detect αSyn and co-occurring Aβ and/or tau pathologies are discussed. Additionally, the αSyn-targeted disease-modifying therapies in clinical trials are summarized.
Vitamin A and Alzheimer's disease Ono, Kenjiro; Yamada, Masahito
Geriatrics & gerontology international,
April 2012, Letnik:
12, Številka:
2
Journal Article
Recenzirano
The deposition of amyloid β‐protein (Aβ) in the brain is an invariant feature of Alzheimer's disease (AD). Vitamin A, which has been traditionally considered an anti‐oxidant compound, plays a role in ...maintaining higher function in the central nervous system. Plasma or cerebrospinal fluid concentrations of vitamin A and β‐carotene have been reported to be lower in AD patients, and these vitamins have been clinically shown to slow the progression of dementia. Vitamin A (retinol, retinal and retinoic acid) and β‐carotene have been shown in in vitro studies to inhibit the formation, extension and destabilizing effects of β‐amyloid fibrils. Recently, the inhibition of the oligomerization of Aβ has been suggested as a possible therapeutic target for the treatment of AD. We have recently shown the inhibitory effects of vitamin A and β‐carotene on the oligomerization of Aβ40 and Aβ42 in vitro. In previous in vivo studies, intraperitoneal injections of vitamin A decreased brain Aβ deposition and tau phosphorylation in transgenic mouse models of AD, attenuated neuronal degeneration, and improved spatial learning and memory. Thus, vitamin A and β‐carotene could be key molecules for the prevention and therapy of AD. Geriatr Gerontol Int 2012; 12: 180–188.
•HS-AFM is able to visualize structural dynamics of individual amyloid aggregates.•Image processing is needed to remove HS-AFM stage drift to analyze the structural dynamics.•ImageJ, a free software, ...can process the HS-AFM data using standard and our plugins.•This method can be applied to any AFM image processing, and is not limited to HS-AFM data.
The structural dynamics of the amyloid protein aggregation process are associated with neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. High-speed atomic force microscopy (HS–AFM) is able to visualize the structural dynamics of individual aggregate species that otherwise cannot be distinguished. HS–AFM observations also detect impurities in the sample, and thus, experiments require relatively high sample purity. To derive valid information regarding the structural dynamics of the sample from the high-speed AFM images, a correction of the influence caused by the drift of the stage (scanner) from all frames is required. However, correcting the HS–AFM videos that consist of a large number of images requires significant effort. Here, using HS–AFM observation of α-synuclein fibril elongation as an example, we propose an HS–AFM image processing procedure to correct stage drift in the x-, y-, and z-directions with the free software ImageJ. ImageJ with default settings and our plugins attached to this article can process and analyze image stacks, which allow users to easily detect and show the temporal change in sample structures. This processing method can be automatically applied to numerous HS–AFM videos by batch processing with a series of ImageJ macrofunctions.
Dietary fibers are metabolized by gastrointestinal (GI) bacteria into short-chain fatty acids (SCFAs). We investigated the potential role of these SCFAs in β-amyloid (Aβ) mediated pathological ...processes that play key roles in Alzheimer's disease (AD) pathogenesis.
Multiple complementary assays were used to investigate individual SCFAs for their dose-responsive effects in interfering with the assembly of Aβß1-40 and Aβ1-42 peptides into soluble neurotoxic Aβ aggregates.
We found that several select SCFAs are capable of potently inhibiting Aβ aggregations, in vitro.
Our studies support the hypothesis that intestinal microbiota may help protect against AD, in part, by supporting the generation of select SCFAs, which interfere with the formation of toxic soluble Aβ aggregates.
Amyloid β-protein (Aβ) oligomers may be the proximate neurotoxins in Alzheimer's disease (AD). "Oligomer" is an ill-defined term because many kinds have been reported and they often exist in rapid ...equilibrium with monomers and higher-order assemblies. We report here results of studies in which specific oligomers have been stabilized structurally, fractionated in pure form, and then studied by using a combination of CD spectroscopy, Thioflavin T fluorescence, EM, atomic force microscopy (AFM), and neurotoxicity assays. Aβ monomers were largely unstructured, but oligomers exhibited order-dependent increases in β-sheet content. EM and AFM data suggest that dimerization and subsequent monomer addition are processes in which significant and asymmetric monomer conformational changes occur. Oligomer secondary structure and order correlated directly with fibril nucleation activity. Neurotoxic activity increased disproportionately (order dependence >1) with oligomer order. The structure-activity correlations reported here significantly extend our understanding of the conformational dynamics, structure, and relative toxicity of pure Aβ oligomers of specific order.
Abstract
The assembly of misfolded proteins into amyloid fibrils is associated with amyloidosis, including neurodegenerative diseases such as Alzheimer’s, Parkinson’s and prion diseases. The ...self-propagation of amyloid fibrils is widely observed in the aggregation pathways of numerous amyloidogenic proteins. This propensity with plasticity in primary nucleation allows amyloid fibril polymorphism, which is correlated with the pathology/phenotypes of patients. Because the interference with the nucleation and replication processes of amyloid fibrils can alter the amyloid structure and the outcome of the disease, these processes can be a target for developing clinical drugs. Single-molecule observations of amyloid fibril replication can be an experimental system to provide the kinetic parameters for simulation studies and confirm the effect of clinical drugs. Here, we review the single-molecule observation of the amyloid fibril replication process using fluorescence microscopy and time-lapse atomic force microscopy, including high-speed atomic force microscopy. We discussed the amyloid fibril replication process and combined single-molecule observation results with molecular dynamics simulations.
Aggregation of amyloidogenic proteins into insoluble amyloid fibrils is implicated in various neurodegenerative diseases. This process involves protein assembly into oligomeric intermediates and ...fibrils with highly polymorphic molecular structures. These structural differences may be responsible for different disease presentations. For this reason, elucidation of the structural features and assembly kinetics of amyloidogenic proteins has been an area of intense study. We report here the results of high-speed atomic force microscopy (HS-AFM) studies of fibril formation and elongation by the 42-residue form of the amyloid β-protein (Aβ1–42), a key pathogenetic agent of Alzheimer’s disease. Our data demonstrate two different growth modes of Aβ1–42, one producing straight fibrils and the other producing spiral fibrils. Each mode depends on initial fibril nucleus structure, but switching from one growth mode to another was occasionally observed, suggesting that fibril end structure fluctuated between the two growth modes. This switching phenomenon was affected by buffer salt composition. Our findings indicate that polymorphism in fibril structure can occur after fibril nucleation and is affected by relatively modest changes in environmental conditions.
Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder and is characterized by pathological aggregates of amyloid β-protein (Aβ) and tau protein. On the basis of genetic ...evidence, biochemical data, and animal models, Aβ has been suggested to be responsible for the pathogenesis of AD (the amyloid hypothesis). Aβ molecules tend to aggregate to form oligomers, protofibrils, and mature fibrils. Although mature fibrils in the final stage have been thought to be the cause of AD pathogenesis, recent studies using synthetic Aβ peptides, a cell culture model, Aβ precursor protein transgenic mice models, and human samples, such as cerebrospinal fluids and postmortem brains of AD patients, suggest that pre-fibrillar forms (oligomers of Aβ) are more deleterious than are extracellular fibril forms. Based on this recent evidence showing that oligomers have a central role in the pathogenesis of AD, the term “oligomeropathy” could be used to define AD and other protein-misfolding diseases.
In this review, I discuss recent developments in the “oligomer hypothesis” including our research findings regarding the pathogenesis of AD.
•Aβ has been suggested to be responsible for the AD pathogenesis (amyloid hypothesis).•Aβ molecules tend to aggregate and form oligomers, protofibrils, and mature fibrils.•Aβ and tau oligomers are more deleterious than are other forms (oligomer hypothesis).•The term “oligomeropathy” could be used to define AD.
Alzheimer's disease (AD), a slow progressive form of dementia, is clinically characterized by cognitive dysfunction and memory impairment and neuropathologically characterized by the accumulation of ...extracellular plaques containing amyloid β-protein (Aβ) and neurofibrillary tangles containing tau in the brain, with neuronal degeneration and high level of oxidative stress. The current treatments for AD, e.g., acetylcholinesterase inhibitors (AChEIs), have efficacies limited to symptom improvement. Although there are various approaches to the disease modifying therapies of AD, none of them can be used alone for actual treatment, and combination therapy may be needed for amelioration of the progression. There are reports that cilostazol (CSZ) suppressed cognitive decline progression in patients with mild cognitive impairment or stable AD receiving AChEIs. Previously, we showed that CSZ suppressed Aβ-induced neurotoxicity in SH-SY5Y cells
coincident inhibition of oxidative stress, as demonstrated by reduced activity of nicotinamide adenine dinucleotide phosphate oxidase, accumulation of reactive oxygen species, and signaling of mitogen-activated protein kinase. CSZ also rescued cognitive impairment and promoted soluble Aβ clearance in a mouse model of cerebral amyloid angiopathy. Mature Aβ fibrils have long been considered the primary neurodegenerative factors in AD; however, recent evidence indicates soluble oligomers to initiate the neuronal and synaptic dysfunction related to AD and other protein-misfolding diseases. Further underscoring the potential of CSZ for AD treatment, we recently described the inhibitory effects of CSZ on Aβ oligomerization and aggregation
. In this review, we discuss the possibility of CSZ as a potential disease-modifying therapy for the prevention or delay of AD.
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