Interactions of amyloid coaggregates with biomolecules and its relevance to neurodegeneration

The aggregation of amyloidogenic proteins is a pathological hallmark of various neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. In these diseases, oligomeric intermediates or toxic aggregates of amyloids cause neuronal damage and degeneration. Despite the substantial effort made over recent decades to implement therapeutic interventions, these neurodegenerative diseases are not yet understood at the molecular level. In many cases, multiple disease-causing amyloids overlap in a sole pathological feature or a sole disease-causing amyloid represents multiple pathological features. Various amyloid pathologies can coexist in the same brain with or without clinical presentation and may even occur in individuals without disease. From sparse data, speculation has arisen regarding the coaggregation of amyloids with disparate amyloid species and other biomolecules, which are the same characteristics that make diagnostics and drug development challenging. However, advances in research related to biomolecular condensates and structural analysis have been used to overcome some of these challenges. Considering the development of these resources and techniques, herein we review the cross-seeding of amyloidosis, for example, involving the amyloids amyloid β, tau, α-synuclein, and human islet amyloid polypeptide, and their cross-inhibition by transthyretin and BRICHOS. The interplay of nucleic acid-binding proteins, such as prions, TAR DNA-binding protein 43, fused in sarcoma/translated in liposarcoma, and fragile X mental retardation polyglycine, with nucleic acids in the pathology of neurodegeneration are also described, and we thereby highlight the potential clinical applications in central nervous system therapy

Pharmacological Potential of Cilostazol for Alzheimer’s Disease

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 via 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 vitro. In this review, we discuss the possibility of CSZ as a potential disease-modifying therapy for the prevention or delay of AD

Anti-Aggregation Effects of Phenolic Compounds on α-Synuclein

The aggregation and deposition of α-synuclein (αS) are major pathologic features of Parkinson\u27s disease, dementia with Lewy bodies, and other α-synucleinopathies. The propagation of αS pathology in the brain plays a key role in the onset and progression of clinical phenotypes. Thus, there is increasing interest in developing strategies that attenuate αS aggregation and propagation. Based on cumulative evidence that αS oligomers are neurotoxic and critical species in the pathogenesis of α-synucleinopathies, we and other groups reported that phenolic compounds inhibit αS aggregation including oligomerization, thereby ameliorating αS oligomer-induced cellular and synaptic toxicities. Heterogeneity in gut microbiota may influence the efficacy of dietary polyphenol metabolism. Our recent studies on the brain-penetrating polyphenolic acids 3-hydroxybenzoic acid (3-HBA), 3,4-dihydroxybenzoic acid (3,4-diHBA), and 3-hydroxyphenylacetic acid (3-HPPA), which are derived from gut microbiota-based metabolism of dietary polyphenols, demonstrated an in vitro ability to inhibit αS oligomerization and mediate aggregated αS-induced neurotoxicity. Additionally, 3-HPPA, 3,4-diHBA, 3-HBA, and 4-hydroxybenzoic acid significantly attenuated intracellular αS seeding aggregation in a cell-based system. This review focuses on recent research developments regarding neuroprotective properties, especially anti-αS aggregation effects, of phenolic compounds and their metabolites by the gut microbiome, including our findings in the pathogenesis of α-synucleinopathies

Gut Microbiome-Modified Polyphenolic Compounds Inhibit α-Synuclein Seeding and Spreading in α-Synucleinopathies

Misfolding, aggregation and deposition of α-synuclein (α-syn) are major pathologic characteristics of Parkinson’s disease (PD) and the related synucleinopathy, multiple system atrophy (MSA). The spread of α-syn pathology across brain regions is thought to play a key role in the onset and progression of clinical phenotypes. Thus, there is increasing interest in developing strategies that target and attenuate α-syn aggregation and spread. Recent studies of brain-penetrating polyphenolic acids, namely, 3-hydroxybenzoic acid (3-HBA), 3,4-dihydroxybenzoic acid (3,4-diHBA), and 3-(3-hydroxyphenyl)propionic acid (3-HPPA) that are derived from gut microbiota metabolism of dietary polyphenols, show in vitro ability to effectively modulate α-syn misfolding, oligomerization, and mediate aggregated α-syn neurotoxicity. Here we investigate whether 3-HBA, 4-hydroxybenzoic acid (4-HBA), 3,4-diHBA, or 3-HPPA interfere with α-syn spreading in a cell-based system. Using HEK293 cells overexpressing α-syn-A53T-CFP/YFP, we assessed α-syn seeding activity using Fluorescence Resonance Energy Transfer (FRET) to detect and quantify α-syn aggregation. We demonstrated that 3-HPPA, 3,4-diHBA, 3-HBA, and 4-HBA significantly attenuated intracellular α-syn seeding aggregation. To determine whether our compounds could inhibit brain-derived seeding activity, we utilized insoluble α-syn extracted from post-mortem MSA or PD brain specimens. We found that 3-HPPA effectively attenuated MSA-induced aggregation of monomer into high molecular weight aggregates capable of inducing intracellular aggregation. Outcomes from our studies suggest interactions between gut microbiome and certain dietary factors may form the basis for effective therapies that modulate pathologic α-syn propagation. Collectively, our findings provide the basis for future developments of probiotic, prebiotic, or synbiotic approaches for modulating the onset and/or progression of α-synucleinopathies

Nanoscale Proximity Effect in the High Temperature Superconductor Bi-2212

High temperature cuprate superconductors exhibit extremely local nanoscale phenomena and strong sensitivity to doping. While other experiments have looked at nanoscale interfaces between layers of different dopings, we focus on the interplay between naturally inhomogeneous nanoscale regions. Using scanning tunneling microscopy to carefully track the same region of the sample as a function of temperature, we show that regions with weak superconductivity can persist to elevated temperatures if bordered by regions of strong superconductivity. This suggests that it may be possible to increase the maximum possible transition temperature by controlling the distribution of dopants.Comment: To appear in Physical Review Letter

生体分子及び有機化合物のαーシヌクレイン凝集に及ぼす影響の解析

金沢大学附属病院α-シヌクレイン蛋白(αS)の凝集は、パーキンソン病やび漫性レビー小体型認知症といったレビー小体病(LBD)や多系統萎縮症(MSA)において、病態形成上重要な役割を果たしていると考えられている。これまで我々はワイン関連ポリフェノールやクルクミンをはじめとする抗酸化物質がアルツハイマー病(AD)βアミロイド線維(fAβ)形成を抑制するだけでなく、既存のfAβを不安定化することを明らかにしてきた(J Neurochem, 2002 ; Biol Psychiatry, 2002 ; J Neurochem, 2003 ; J Neurosci Res, 2004 ; Biochim Biophys Acta, 2004 ; Exp Neurol, 2004 : Neurochem Int, 2006)。今回、我々は蛍光色素チオフラビンS(ThS)法、電子顕微鏡、原子間顕微鏡等を主に用いて試験管内α-シヌクレイン線維(fαS)形成・分解機構解明のための基本モデルを開発・確立し、このモデルを用いてfαS形成・不安定化過程に及ぼす様々な有機化合物の影響を解析した。その結果、ワイン関連ポリフェノールやクルクミン、ローズマリー酸(J Neurochem,2006)、ビタミンA類(Neurobiol Dis,2007)、セレギリンをはじめとする抗パーキンソン病薬(J Neurosci Res, in press)がfAβに対する作用と同様にfαS形成を抑制し、さらに既存のfαSも不安定化させることを明らかにし、これらの分子がLBDやMSAの予防薬や治療薬開発に向けて有力な基本分子になる可能性があることを提案した。さらに、外来で得られたLBD患者等の生体試料を用いてLBD患者の脳脊髄液はnon-CNS disease患者に比較してfαS形成を促進するが、AD患者の脳脊髄液も同様に促進傾向を示し、ADとLBDの間では有意な差はないことを明らかにした(Exp Neurol,2007)。研究課題/領域番号:18790589, 研究期間(年度):2006 – 2007出典：「生体分子及び有機化合物のαーシヌクレイン凝集に及ぼす影響の解析」研究成果報告書　課題番号18790589（KAKEN：科学研究費助成事業データベース（国立情報学研究所））（https://kaken.nii.ac.jp/ja/grant/KAKENHI-PROJECT-18790589/)を加工して作

ノルジヒドログアイアレチン酸はアルツハイマー病βアミロイド線維を強力に分解する

取得学位 : 博士（医学）, 学位授与番号 : 医博甲第1548号, 学位授与年月日 : 平成14年9月30日, 学位授与大学 : 金沢大

Cross-seeding effects of amyloid β-protein and α-synuclein

Amyloid β-protein (Aβ) and α-synuclein (αS) are the primary components of amyloid plaques and Lewy bodies (LBs), respectively. Previous in vitro and in vivo studies have suggested that interactions between Aβ and αS are involved in the pathogenesis of Alzheimer\u27s disease and LB diseases. However, the seeding effects of their aggregates on their aggregation pathways are not completely clear. To investigate the cross-seeding effects of Aβ and αS, we examined how sonicated fibrils or cross-linked oligomers of Aβ40, Aβ42, and αS affected their aggregation pathways using thioflavin T(S) assay and electron microscopy. Fibrils and oligomers of Aβ40, Aβ42, and αS acted as seeds, and affected the aggregation pathways within and among species. The seeding effects of αS fibrils were higher than those of Aβ40 and Aβ42 fibrils in the Aβ40 and Aβ42 aggregation pathways, respectively. We showed that Aβ and αS acted as seeds and affected each other\u27s aggregation pathways in vitro, which may contribute to our understanding of the molecular mechanisms of interactions between Alzheimer\u27s disease and LB diseases pathologies. © 2012 The Authors