Multifunctional carbon dots as a therapeutic nanoagent for modulating Cu(ii)-mediated β-amyloid aggregation

Nanoscale ◽  
2019 ◽  
Vol 11 (13) ◽  
pp. 6297-6306 ◽  
Author(s):  
You Jung Chung ◽  
Byung Il Lee ◽  
Chan Beum Park
Keyword(s):  
Carbon Dots ◽  
Amyloid Aggregation ◽  
Aβ Peptides ◽  
Aβ Aggregation ◽  
Amyloid Aβ ◽  
Β Amyloid

Multifunctional carbon dots are synthesized to chelate Cu(ii) ions, suppress Alzheimer's β-amyloid (Aβ) aggregation, and photooxygenate Aβ peptides.

scholarly journals KLOTHO heterozygosity attenuates APOE4-related amyloid burden in preclinical AD

Neurology ◽  
2019 ◽  
Vol 92 (16) ◽  
pp. e1878-e1889 ◽  
Author(s):  
Claire M. Erickson ◽  
Stephanie A. Schultz ◽  
Jennifer M. Oh ◽  
Burcu F. Darst ◽  
Yue Ma ◽  
...  
Keyword(s):  
Disease Onset ◽  
Regression Analyses ◽  
Middle Aged ◽  
Pittsburgh Compound B ◽  
Preclinical Ad ◽  
Aβ Aggregation ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
Middle Aged Adults

ObjectiveTo examine whether the KLOTHO gene variant KL-VS attenuates APOE4-associated β-amyloid (Aβ) accumulation in a late-middle-aged cohort enriched with Alzheimer disease (AD) risk factors.MethodsThree hundred nine late-middle-aged adults from the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center were genotyped to determine KL-VS and APOE4 status and underwent CSF sampling (n = 238) and/or 11C-Pittsburgh compound B (PiB)-PET imaging (n = 183). Covariate-adjusted regression analyses were used to investigate whether APOE4 exerted expected effects on Aβ burden. Follow-up regression analyses stratified by KL-VS genotype (i.e., noncarrier vs heterozygous; there were no homozygous individuals) evaluated whether the influence of APOE4 on Aβ was different among KL-VS heterozygotes compared to noncarriers.ResultsAPOE4 carriers exhibited greater Aβ burden than APOE4-negative participants. This effect was stronger in CSF (t = −5.12, p < 0.001) compared with PiB-PET (t = 3.93, p < 0.001). In the stratified analyses, this APOE4 effect on Aβ load was recapitulated among KL-VS noncarriers (CSF: t = −5.09, p < 0.001; PiB-PET: t = 3.77, p < 0 .001). In contrast, among KL-VS heterozygotes, APOE4-positive individuals did not exhibit higher Aβ burden than APOE4-negative individuals (CSF: t = −1.03, p = 0.308; PiB-PET: t = 0.92, p = 0.363). These differential APOE4 effects remained after KL-VS heterozygotes and noncarriers were matched on age and sex.ConclusionIn a cohort of at-risk late-middle-aged adults, KL-VS heterozygosity was associated with an abatement of APOE4-associated Aβ aggregation, suggesting KL-VS heterozygosity confers protections against APOE4-linked pathways to disease onset in AD.

scholarly journals The Function of Transthyretin Complexes with Metallothionein in Alzheimer’s Disease

2020 ◽  
Vol 21 (23) ◽  
pp. 9003
Author(s):  
Natalia Zaręba ◽  
Marta Kepinska
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cortical Neurons ◽  
The Elderly ◽  
Pathological Feature ◽  
Aβ Peptides ◽  
Treatment And Prevention ◽  
Aβ Aggregation ◽  
Cultured Cortical Neurons ◽  
Amyloid Aβ

Alzheimer’s disease (AD) is one of the most frequently diagnosed types of dementia in the elderly. An important pathological feature in AD is the aggregation and deposition of the β-amyloid (Aβ) in extracellular plaques. Transthyretin (TTR) can cleave Aβ, resulting in the formation of short peptides with less activity of amyloid plaques formation, as well as being able to degrade Aβ peptides that have already been aggregated. In the presence of TTR, Aβ aggregation decreases and toxicity of Aβ is abolished. This may prevent amyloidosis but the malfunction of this process leads to the development of AD. In the context of Aβplaque formation in AD, we discuss metallothionein (MT) interaction with TTR, the effects of which depend on the type of MT isoform. In the brains of patients with AD, the loss of MT-3 occurs. On the contrary, MT-1/2 level has been consistently reported to be increased. Through interaction with TTR, MT-2 reduces the ability of TTR to bind to Aβ, while MT-3 causes the opposite effect. It increases TTR-Aβ binding, providing inhibition of Aβ aggregation. The protective effect, assigned to MT-3 against the deposition of Aβ, relies also on this mechanism. Additionally, both Zn7MT-2 and Zn7MT-3, decrease Aβ neurotoxicity in cultured cortical neurons probably because of a metal swap between Zn7MT and Cu(II)Aβ. Understanding the molecular mechanism of metals transfer between MT and other proteins as well as cognition of the significance of TTR interaction with different MT isoforms can help in AD treatment and prevention.

scholarly journals Natural Scaffolds with Multi-Target Activity for the Potential Treatment of Alzheimer’s Disease

Molecules ◽  
2018 ◽  
Vol 23 (9) ◽  
pp. 2182 ◽  
Author(s):  
Luca Piemontese ◽  
Gabriele Vitucci ◽  
Marco Catto ◽  
Antonio Laghezza ◽  
Filippo Perna ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Structural Characteristics ◽  
Biological Properties ◽  
Cognitive Capacity ◽  
Aβ Aggregation ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
Ad Therapy ◽  
Target Activity

A few symptomatic drugs are currently available for Alzheimer’s Disease (AD) therapy, but these molecules are only able to temporary improve the cognitive capacity of the patients if administered in the first stages of the pathology. Recently, important advances have been achieved about the knowledge of this complex condition, which is now considered a multi-factorial disease. Researchers are, thus, more oriented toward the preparation of molecules being able to contemporaneously act on different pathological features. To date, the inhibition of acetylcholinesterase (AChE) and of β-amyloid (Aβ) aggregation as well as the antioxidant activity and the removal and/or redistribution of metal ions at the level of the nervous system are the most common investigated targets for the treatment of AD. Since many natural compounds show multiple biological properties, a series of secondary metabolites of plants or fungi with suitable structural characteristics have been selected and assayed in order to evaluate their potential role in the preparation of multi-target agents. Out of six compounds evaluated, 1 showed the best activity as an antioxidant (EC50 = 2.6 ± 0.2 μmol/µmol of DPPH) while compound 2 proved to be effective in the inhibition of AChE (IC50 = 6.86 ± 0.67 μM) and Aβ1–40 aggregation (IC50 = 74 ± 1 μM). Furthermore, compound 6 inhibited BChE (IC50 = 1.75 ± 0.59 μM) with a good selectivity toward AChE (IC50 = 86.0 ± 15.0 μM). Moreover, preliminary tests on metal chelation suggested a possible interaction between compounds 1, 3 and 4 and copper (II). Molecules with the best multi-target profiles will be used as starting hit compounds to appropriately address future studies of Structure-Activity Relationships (SARs).

scholarly journals 9-Methylfascaplysin Is a More Potent Aβ Aggregation Inhibitor than the Marine-Derived Alkaloid, Fascaplysin, and Produces Nanomolar Neuroprotective Effects in SH-SY5Y Cells

Marine Drugs ◽  
2019 ◽  
Vol 17 (2) ◽  
pp. 121 ◽  
Author(s):  
Qingmei Sun ◽  
Fufeng Liu ◽  
Jingcheng Sang ◽  
Miaoman Lin ◽  
Jiale Ma ◽  
...  
Keyword(s):  
Amino Acid Residues ◽  
Neuroprotective Effects ◽  
Study Results ◽  
Aβ Aggregation ◽  
Aggregation Inhibitors ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
Dynamics Simulations ◽  
Aβ Oligomer

β-Amyloid (Aβ) is regarded as an important pathogenic target for Alzheimer’s disease (AD), the most prevalent neurodegenerative disease. Aβ can assemble into oligomers and fibrils, and produce neurotoxicity. Therefore, Aβ aggregation inhibitors may have anti-AD therapeutic efficacies. It was found, here, that the marine-derived alkaloid, fascaplysin, inhibits Aβ fibrillization in vitro. Moreover, the new analogue, 9-methylfascaplysin, was designed and synthesized from 5-methyltryptamine. Interestingly, 9-methylfascaplysin is a more potent inhibitor of Aβ fibril formation than fascaplysin. Incubation of 9-methylfascaplysin with Aβ directly reduced Aβ oligomer formation. Molecular dynamics simulations revealed that 9-methylfascaplysin might interact with negatively charged residues of Aβ42 with polar binding energy. Hydrogen bonds and π–π interactions between the key amino acid residues of Aβ42 and 9-methylfascaplysin were also suggested. Most importantly, compared with the typical Aβ oligomer, Aβ modified by nanomolar 9-methylfascaplysin produced less neuronal toxicity in SH-SY5Y cells. 9-Methylfascaplysin appears to be one of the most potent marine-derived compounds that produces anti-Aβ neuroprotective effects. Given previous reports that fascaplysin inhibits acetylcholinesterase and induces P-glycoprotein, the current study results suggest that fascaplysin derivatives can be developed as novel anti-AD drugs that possibly act via inhibition of Aβ aggregation along with other target mechanisms.

scholarly journals Following spatial Aβ aggregation dynamics in evolving Alzheimer’s disease pathology by imaging stable isotope labeling kinetics

2021 ◽  
Vol 7 (25) ◽  
pp. eabg4855
Author(s):  
Wojciech Michno ◽  
Katie M. Stringer ◽  
Thomas Enzlein ◽  
Melissa K. Passarelli ◽  
Stephane Escrig ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mass Spectrometry Imaging ◽  
Isotope Labeling ◽  
Brain Regions ◽  
Plaque Development ◽  
Aβ Aggregation ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
Detailed Picture

β-Amyloid (Aβ) plaque formation is the major pathological hallmark of Alzheimer’s disease (AD) and constitutes a potentially critical, early inducer driving AD pathogenesis as it precedes other pathological events and cognitive symptoms by decades. It is therefore critical to understand how Aβ pathology is initiated and where and when distinct Aβ species aggregate. Here, we used metabolic isotope labeling in APPNL-G-F knock-in mice together with mass spectrometry imaging to monitor the earliest seeds of Aβ deposition through ongoing plaque development. This allowed visualizing Aβ aggregation dynamics within single plaques across different brain regions. We show that formation of structurally distinct plaques is associated with differential Aβ peptide deposition. Specifically, Aβ1-42 is forming an initial core structure followed by radial outgrowth and late secretion and deposition of Aβ1-38. These data describe a detailed picture of the earliest events of precipitating amyloid pathology at scales not previously possible.

scholarly journals Transmissible Endosomal Intoxication: A Balance between Exosomes and Lysosomes at the Basis of Intercellular Amyloid Propagation

Biomedicines ◽  
2020 ◽  
Vol 8 (8) ◽  
pp. 272
Author(s):  
Anaïs Bécot ◽  
Charlotte Volgers ◽  
Guillaume van Niel
Keyword(s):  
Amyloid Precursor Protein ◽  
Neurodegenerative Diseases ◽  
Multivesicular Body ◽  
Precursor Protein ◽  
Aβ Peptides ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
Novel Concept ◽  
The Brain

In Alzheimer′s disease (AD), endolysosomal dysfunctions are amongst the earliest cellular features to appear. Each organelle of the endolysosomal system, from the multivesicular body (MVB) to the lysosome, contributes to the homeostasis of amyloid precursor protein (APP) cleavage products including β-amyloid (Aβ) peptides. Hence, this review will attempt to disentangle how changes in the endolysosomal system cumulate to the generation of toxic amyloid species and hamper their degradation. We highlight that the formation of MVBs and the generation of amyloid species are closely linked and describe how the molecular machineries acting at MVBs determine the generation and sorting of APP cleavage products towards their degradation or release in association with exosomes. In particular, we will focus on AD-related distortions of the endolysomal system that divert it from its degradative function to favour the release of exosomes and associated amyloid species. We propose here that such an imbalance transposed at the brain scale poses a novel concept of transmissible endosomal intoxication (TEI). This TEI would initiate a self-perpetuating transmission of endosomal dysfunction between cells that would support the propagation of amyloid species in neurodegenerative diseases.

Phenylpropanoids and lignans from Prunus tomentosa seeds as efficient β-amyloid (Aβ) aggregation inhibitors

2019 ◽  
Vol 84 ◽  
pp. 269-275 ◽  
Author(s):  
Qingbo Liu ◽  
Jie Wang ◽  
Bin Lin ◽  
Zhuo-Yang Cheng ◽  
Ming Bai ◽  
...  
Keyword(s):  
Aβ Aggregation ◽  
Aggregation Inhibitors ◽  
Amyloid Aβ ◽  
Β Amyloid
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