scholarly journals Large Amino Acid Mimicking Selenium-Doped Carbon Quantum Dots for Multi-Target Therapy of Alzheimer’s Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Xi Zhou ◽  
Shuyang Hu ◽  
Shuangling Wang ◽  
Yu Pang ◽  
Yulong Lin ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Quantum Dots ◽  
Amino Acid ◽  
Target Therapy ◽  
Antioxidant Properties ◽  
Amyloid Β ◽  
Carbon Quantum Dots ◽  
Ros Scavenging ◽  
Aβ Aggregation

Multi-target intervention and synergistic treatment are critical for the drug development of Alzheimer’s disease (AD) due to its complex and multifactional nature. Oxidative stress and amyloid β peptides (Aβ) accumulation have been recognized as therapeutic targets for AD. Herein, with ability to inhibit Aβ aggregation and the broad-spectrum antioxidant properties, the large amino acid mimicking selenium-doped carbon quantum dots (SeCQDs) are presented as novel nanoagents for multi-target therapy of AD. Compared with the precursor, selenocystine, SeCQDs which maintain the intrinsic properties of both selenium and carbon quantum dots (CQDs) possess good biocompatibility and a remarkable ROS-scavenging activity. Moreover, the functionalized α-carboxyl and amino groups on edge of SeCQDs can trigger multivalent interactions with Aβ, leading to the ability of SeCQDs to inhibit Aβ aggregation. In vivo study demonstrated that SeCQDs can significantly ameliorate the Aβ induced memory deficits, reduce Aβ accumulation and inhibit neuron degeneration in AD model rats. The versatility of functionalization and potential ability to cross the blood-brain barrier (BBB) make SeCQDs as prospective nanodrugs for treating AD.

scholarly journals Cu-Based Turn-on Fluorescent Sensors for Cu-rich Amyloid β Aggregates

2021 ◽  
Author(s):  
Yiran Huang ◽  
Liang Sun ◽  
Liviu M. Mirica
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Fluorescence Imaging ◽  
Protein Misfolding ◽  
Picolinic Acid ◽  
Amyloid Β ◽  
Fluorescent Sensors ◽  
Aβ Oligomers ◽  
Turn On ◽  
Aβ Aggregation

<div>Protein misfolding and metal dishomeostasis are two key</div><div>pathological factors of Alzheimer’s disease. Previous studies have showed that Cu‐mediated Aβ aggregation pathways lead to formation of neurotoxic Aβ oligomers. Herein, we reported a series of picolinic acid‐based Cu‐activatable sensors, which can be used for the fluorescence imaging of Cu‐rich Aβ aggregates.</div>

scholarly journals Revisiting the Amyloid Cascade Hypothesis: From Anti-Aβ Therapeutics to Auspicious New Ways for Alzheimer’s Disease

2020 ◽  
Vol 21 (16) ◽  
pp. 5858 ◽  
Author(s):  
Md. Sahab Uddin ◽  
Md. Tanvir Kabir ◽  
Md. Sohanur Rahman ◽  
Tapan Behl ◽  
Philippe Jeandet ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Clinical Symptoms ◽  
Neurodegenerative Disorder ◽  
Early Stage ◽  
Amyloid Β ◽  
Aβ Oligomers ◽  
Aβ Aggregation ◽  
Clinical Benefits

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder related to age, characterized by the cerebral deposition of fibrils, which are made from the amyloid-β (Aβ), a peptide of 40–42 amino acids. The conversion of Aβ into neurotoxic oligomeric, fibrillar, and protofibrillar assemblies is supposed to be the main pathological event in AD. After Aβ accumulation, the clinical symptoms fall out predominantly due to the deficient brain clearance of the peptide. For several years, researchers have attempted to decline the Aβ monomer, oligomer, and aggregate levels, as well as plaques, employing agents that facilitate the reduction of Aβ and antagonize Aβ aggregation, or raise Aβ clearance from brain. Unluckily, broad clinical trials with mild to moderate AD participants have shown that these approaches were unsuccessful. Several clinical trials are running involving patients whose disease is at an early stage, but the preliminary outcomes are not clinically impressive. Many studies have been conducted against oligomers of Aβ which are the utmost neurotoxic molecular species. Trials with monoclonal antibodies directed against Aβ oligomers have exhibited exciting findings. Nevertheless, Aβ oligomers maintain equivalent states in both monomeric and aggregation forms; so, previously administered drugs that precisely decrease Aβ monomer or Aβ plaques ought to have displayed valuable clinical benefits. In this article, Aβ-based therapeutic strategies are discussed and several promising new ways to fight against AD are appraised.

scholarly journals Annona atemoya leaf extract ameliorates cognitive impairment in amyloid-β injected Alzheimer’s disease-like mouse model

2019 ◽  
Vol 244 (18) ◽  
pp. 1665-1679 ◽  
Author(s):  
Hye-Sun Lim ◽  
Yu Jin Kim ◽  
Eunjin Sohn ◽  
Jiyeon Yoon ◽  
Bu-Yeo Kim ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neuronal Cell Death ◽  
Growth Factor Receptor ◽  
Amyloid Β ◽  
Neuronal Cell ◽  
Bioactive Compound ◽  
Aβ Aggregation ◽  
Epidermal Growth ◽  
G Protein Coupled

Annona atemoya is a hybrid of Annona squamosa and Annona cherimola that grow in several subtropical or tropical areas such as Florida in the US, Philippines, Cuba, Jamaica, Taiwan, and Jeju in South Korea. We report that the A. atemoya leaves (AAL) have inhibitory effects on the pathogenesis and regulatory mechanisms of Alzheimer’s disease (AD). Ethanol extract of AAL prevented amyloid-β (Aβ) aggregation and increased free radical scavenging activity. In addition, AAL extract exerted protective effects against neuronal cell death in HT22 hippocampal cells. Moreover, oral administration of AAL extract significantly improved memory loss in the passive avoidance task and Y-maze test, as well as downregulated the expression of neuronal markers neuronal nuclei and brain-derived neurotrophic factor in Aβ-injected AD mice. To verify the molecular mechanisms responsible for anti-AD actions of AAL, we conducted the antibody microarray analysis and found that epidermal growth factor receptor/G protein-coupled receptor kinase 2 signaling was activated in neuronal cells and AD-like mouse models. Additionally, quantitative analyses of the six standard compounds using high-performance liquid chromatography revealed that rutin is the most abundant compound of AAL. Furthermore, efficacy analyses of six standard compounds showed that rutin and isoquercitrin had significant inhibitory activity on Aβ aggregation. Taken together with biological activity and the content of compounds, rutin maybe a bioactive compound of AAL in the AD pathogenesis. Overall, our findings provide the first scientific support for the therapeutic effects of AAL in AD and AD-related disorders. Impact statement Our study was aimed to find a novel candidate drug for Alzheimer’s disease (AD) using natural products. We assessed the effects of Annona atemoya extracts on crucial events in the pathogenesis of AD. A. atemoya leaf (AAL) extract significantly inhibited amyloid-β aggregation, oxidative stress, neuronal cell death, and memory impairment through the epidermal growth factor receptor/G protein-coupled receptor kinase 2 pathway. Simultaneous analysis using HPLC determined six standard compounds of AAL extract, and rutin was identified as a bioactive compound. Of note, the anti-AD activity of AAL extract was more significant compared to other extracts from medicinal plants of which efficacy was previously reported. The potential of AAL extract as an anti-AD agent may provide insight into the new drug development for AD treatment.

scholarly journals TDP-43 interacts with amyloid-β, inhibits fibrillization, and worsens pathology in a model of Alzheimer’s disease

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Yao-Hsiang Shih ◽  
Ling-Hsien Tu ◽  
Ting-Yu Chang ◽  
Kiruthika Ganesan ◽  
Wei-Wei Chang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Long Term Potentiation ◽  
Model Of Alzheimer’S Disease ◽  
Term Potentiation ◽  
Spatial Memory Deficit ◽  
Aβ Aggregation ◽  
Intrahippocampal Injection

AbstractTDP-43 inclusions are found in many Alzheimer’s disease (AD) patients presenting faster disease progression and greater brain atrophy. Previously, we showed full-length TDP-43 forms spherical oligomers and perturbs amyloid-β (Aβ) fibrillization. To elucidate the role of TDP-43 in AD, here, we examined the effect of TDP-43 in Aβ aggregation and the attributed toxicity in mouse models. We found TDP-43 inhibited Aβ fibrillization at initial and oligomeric stages. Aβ fibrillization was delayed specifically in the presence of N-terminal domain containing TDP-43 variants, while C-terminal TDP-43 was not essential for Aβ interaction. TDP-43 significantly enhanced Aβ’s ability to impair long-term potentiation and, upon intrahippocampal injection, caused spatial memory deficit. Following injection to AD transgenic mice, TDP-43 induced inflammation, interacted with Aβ, and exacerbated AD-like pathology. TDP-43 oligomers mostly colocalized with intracellular Aβ in the brain of AD patients. We conclude that TDP-43 inhibits Aβ fibrillization through its interaction with Aβ and exacerbates AD pathology.

scholarly journals Impact of Four Common Hydrogels on Amyloid-β (Aβ) Aggregation and Cytotoxicity: Implications for 3D Models of Alzheimer’s Disease

ACS Omega ◽  
2020 ◽  
Vol 5 (32) ◽  
pp. 20250-20260
Author(s):  
Laura W. Simpson ◽  
Gregory L. Szeto ◽  
Hacene Boukari ◽  
Theresa A. Good ◽  
Jennie B. Leach
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
3D Models ◽  
Aβ Aggregation

scholarly journals In vitro studies of amyloid β-protein fibril assembly and toxicity provide clues to the aetiology of Flemish variant (Ala692→Gly) Alzheimer's disease

2001 ◽  
Vol 355 (3) ◽  
pp. 869-877 ◽  
Author(s):  
Dominic M. WALSH ◽  
Dean M. HARTLEY ◽  
Margaret M. CONDRON ◽  
Dennis J. SELKOE ◽  
David B. TEPLOW
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amino Acid ◽  
Amino Acid Substitution ◽  
Amyloid Β ◽  
In Vitro Studies ◽  
Amyloid Β Protein ◽  
Wild Type ◽  
Β Protein

In a Flemish kindred, an Ala692 → Gly amino acid substitution in the amyloid β-protein precursor (AβPP) causes a form of early-onset Alzheimer's disease (AD) which displays prominent amyloid angiopathy and unusually large senile plaque cores. The mechanistic basis of this Flemish form of AD is unknown. Previous in vitro studies of amyloid β-protein (Aβ) production in HEK-293 cells transfected with cDNA encoding Flemish AβPP have shown that full-length [Aβ(1–40)] and truncated [Aβ(5–40) and Aβ(11–40)] forms of Aβ are produced. In an effort to determine how these peptides might contribute to the pathogenesis of the Flemish disease, comparative biophysical and neurotoxicity studies were performed on wild-type and Flemish Aβ(1–40), Aβ(5–40) and Aβ(11–40). The results revealed that the Flemish amino acid substitution increased the solubility of each form of peptide, decreased the rate of formation of thioflavin-T-positive assemblies, and increased the SDS-stability of peptide oligomers. Although the kinetics of peptide assembly were altered by the Ala21 → Gly substitution, all three Flemish variants formed fibrils, as did the wild-type peptides. Importantly, toxicity studies using cultured primary rat cortical cells showed that the Flemish assemblies were as potent a neurotoxin as were the wild-type assemblies. Our results are consistent with a pathogenetic process in which conformational changes in Aβ induced by the Ala21 → Gly substitution would facilitate peptide adherence to the vascular endothelium, creating nidi for amyloid growth. Increased peptide solubility and assembly stability would favour formation of larger deposits and inhibit their elimination. In addition, increased concentrations of neurotoxic assemblies would accelerate neuronal injury and death.

Alzheimer's Disease: Progress in the Development of Anti-amyloid Disease-Modifying Therapies

CNS Spectrums ◽  
2007 ◽  
Vol 12 (2) ◽  
pp. 113-123 ◽  
Author(s):  
Daniel D. Christensen
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Amyloid Β ◽  
Phase Iii ◽  
Peroxisome Proliferator ◽  
Serious Adverse Events ◽  
Amyloid Disease ◽  
Aβ Aggregation ◽  
Disease Modifying

ABSTRACTThe amyloid hypothesis—the leading mechanistic theory of Alzheimer's disease—states that an imbalance in production or clearance of amyloid β (Aβ) results in accumulation of Aβ and triggers a cascade of events leading to neurodegeneration and dementia. The number of persons with Alzheimer's disease is expected to triple by mid-century. If steps are not taken to delay the onset or slow the progression of Alzheimer's disease, the economic and personal tolls will be immense. Different classes of potentially disease-modifying treatments that interrupt early pathological events (ie, decreasing production or aggregation of Aβ or increasing its clearance) and potentially prevent downstream events are in phase II or III clinical studies. These include immunotherapies; secretase inhibitors; selective Aβ42-lowering agents; statins; anti-Aβ aggregation agents; peroxisome proliferator-activated receptor-gamma agonists; and others. Safety and serious adverse events have been a concern with immunotherapy and γ-secretase inhibitors, though both continue in clinical trials. Anti-amyloid disease-modifying drugs that seem promising and have reached phase III clinical trials include those that selectively target Aβ42 production (eg, tarenflurbil), enhance the activity of α-secretase (eg, statins), and block Aβ aggregation (eg, transiposate).

scholarly journals Simultaneous Quantification of Four Marker Compounds in Bauhinia coccinea Extract and Their Potential Inhibitory Effects on Alzheimer’s Disease Biomarkers

Plants ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 702
Author(s):  
Yu Jin Kim ◽  
Eunjin Sohn ◽  
Hye-Sun Lim ◽  
Yoonju Kim ◽  
Joo-Hwan Kim ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Gallic Acid ◽  
Biological Activities ◽  
Amyloid Β ◽  
Neuronal Cell ◽  
Interactive Effects ◽  
Inhibitory Effects ◽  
Aβ Aggregation ◽  
Marker Compounds

Bauhinia coccinea is a tropical woody plant widely distributed in Vietnam and Unnan in southern China. Although many studies have shown the biological activities of extracts from various other species in the genus, no studies have investigated the effects of B. coccinea extracts on biological systems. In the present study, a quantitative analysis of four marker compounds of ethanol extracts of B. coccinea branches (EEBC) was performed using the high performance liquid chromatography (HPLC)-photodiode array (PDA) method. Among gallic acid, (+)-catechin, ellagic acid, and quercitrin contained in EEBC, the most abundant compound was (+)-catechin (18.736 mg/g). In addition, we investigated the EEBC on neuroprotection, antioxidation, and Alzheimer’s disease (AD) marker molecules, acetylcholinesterase (AChE), and amyloid-β (Aβ). EEBC significantly inhibited hydrogen peroxide (H2O2)-induced cell death in a HT22 neuronal cell line and increased 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) and 2,2-diphenyl-1-picrylhydrazyl scavenging activity markedly. EEBC also inhibited AChE and Aβ aggregation. Among the four compounds, gallic acid exhibited strong inhibitory effects against AChE activation. In the Aβ aggregation assay, the four marker compounds exhibited inhibitory effects lower than 30%. According to the results, EEBC could exert anti-AChE activation and Aβ aggregation activities based on the interactive effects of the marker compounds. Our findings suggest that EEBC are sources of therapeutic candidates for application in the development of AD medication based on AChE and Aβ dual targeting.

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