scholarly journals Natural Compounds as Inhibitors of Aβ Peptide Aggregation: Chemical Requirements and Molecular Mechanisms

2020 ◽  
Vol 14 ◽  
Author(s):  
Katiuscia Pagano ◽  
Simona Tomaselli ◽  
Henriette Molinari ◽  
Laura Ragona
Keyword(s):  
Molecular Weight ◽  
Molecular Mechanisms ◽  
Amyloid Β ◽  
Natural Compounds ◽  
Preventive Therapy ◽  
Small Subset ◽  
Aβ Peptide ◽  
Aβ Oligomers ◽  
Chemical Structures ◽  
The Brain

Alzheimer’s disease (AD) is one of the most common neurodegenerative disorders, with no cure and preventive therapy. Misfolding and extracellular aggregation of Amyloid-β (Aβ) peptides are recognized as the main cause of AD progression, leading to the formation of toxic Aβ oligomers and to the deposition of β-amyloid plaques in the brain, representing the hallmarks of AD. Given the urgent need to provide alternative therapies, natural products serve as vital resources for novel drugs. In recent years, several natural compounds with different chemical structures, such as polyphenols, alkaloids, terpenes, flavonoids, tannins, saponins and vitamins from plants have received attention for their role against the neurodegenerative pathological processes. However, only for a small subset of them experimental evidences are provided on their mechanism of action. This review focuses on those natural compounds shown to interfere with Aβ aggregation by direct interaction with Aβ peptide and whose inhibitory mechanism has been investigated by means of biophysical and structural biology experimental approaches. In few cases, the combination of approaches offering a macroscopic characterization of the oligomers, such as TEM, AFM, fluorescence, together with high-resolution methods could shed light on the complex mechanism of inhibition. In particular, solution NMR spectroscopy, through peptide-based and ligand-based observation, was successfully employed to investigate the interactions of the natural compounds with both soluble NMR-visible (monomer and low molecular weight oligomers) and NMR-invisible (high molecular weight oligomers and protofibrils) species. The molecular determinants of the interaction of promising natural compounds are here compared to infer the chemical requirements of the inhibitors and the common mechanisms of inhibition. Most of the data converge to indicate that the Aβ regions relevant to perturb the aggregation cascade and regulate the toxicity of the stabilized oligomers, are the N-term and β1 region. The ability of the natural aggregation inhibitors to cross the brain blood barrier, together with the tactics to improve their low bioavailability are discussed. The analysis of the data ensemble can provide a rationale for the selection of natural compounds as molecular scaffolds for the design of new therapeutic strategies against the progression of early and late stages of AD.

Recent Advances in Multi-target Anti-Alzheimer Disease Compounds (2013 Up to the Present)

2019 ◽  
Vol 26 (30) ◽  
pp. 5684-5710 ◽  
Author(s):  
Ning Wang ◽  
Panpan Qiu ◽  
Wei Cui ◽  
Xiaojun Yan ◽  
Bin Zhang ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Chemical Structures ◽  
Target Drug ◽  
Single Target ◽  
Approved Drugs ◽  
Multiple Drugs ◽  
Fda Approved Drugs ◽  
Ad Therapy

: Since the last century, when scientists proposed the lock-and-key model, the discovery of drugs has focused on the development of drugs acting on single target. However, single-target drug therapies are not effective to complex diseases with multi-factorial pathogenesis. Moreover, the combination of single-target drugs readily causes drug resistance and side effects. In recent years, multi-target drugs have increasingly been represented among FDA-approved drugs. Alzheimer’s Disease (AD) is a complex and multi-factorial disease for which the precise molecular mechanisms are still not fully understood. In recent years, rational multi-target drug design methods, which combine the pharmacophores of multiple drugs, have been increasingly applied in the development of anti-AD drugs. In this review, we give a brief description of the pathogenesis of AD and provide detailed discussions about the recent development of chemical structures of anti-AD agents (2013 up to present) that have multiple targets, such as amyloid-β peptide, Tau protein, cholinesterases, monoamine oxidase, β-site amyloid-precursor protein-cleaving enzyme 1, free radicals, metal ions (Fe2+, Cu2+, Zn2+) and so on. In this paper, we also added some novel targets or possible pathogenesis which have been reported in recent years for AD therapy. We hope that these findings may provide new perspectives for the pharmacological treatment of AD.

scholarly journals Effects of Red Ginseng on Neural Injuries with Reference to the Molecular Mechanisms

J ◽  
2019 ◽  
Vol 2 (2) ◽  
pp. 116-127
Author(s):  
Pengxiang Zhu ◽  
Masahiro Sakanaka
Keyword(s):  
Molecular Mechanisms ◽  
Bioactive Molecules ◽  
Red Ginseng ◽  
Promising Candidate ◽  
Neuroprotective Effects ◽  
Chemical Structures ◽  
Brain And Spinal Cord ◽  
The Brain

Red ginseng, as an effective herbal medicine, has been traditionally and empirically used for the treatment of neuronal diseases. Many studies suggest that red ginseng and its ingredients protect the brain and spinal cord from neural injuries such as ischemia, trauma, and neurodegeneration. This review focuses on the molecular mechanisms underlying the neuroprotective effects of red ginseng and its ingredients. Ginsenoside Rb1 and other ginsenosides are regarded as the active ingredients of red ginseng; the anti-apoptotic, anti-inflammatory, and anti-oxidative actions of ginsenosides, together with a series of bioactive molecules relevant to the above actions, appear to account for the neuroprotective effects in vivo and/or in vitro. Moreover, in this review, the possibility is raised that more effective or stable neuroprotective derivatives based on the chemical structures of ginsenosides could be developed. Although further studies, including clinical trials, are necessary to confirm the pharmacological properties of red ginseng and its ingredients, red ginseng and its ingredients could be promising candidate drugs for the treatment of neural injuries.

scholarly journals Fluorine-19 Magnetic Resonance Imaging for Detection of Amyloid β Oligomers Using a Keto Form of Curcumin Derivative in a Mouse Model of Alzheimer’s Disease

Molecules ◽  
2021 ◽  
Vol 26 (5) ◽  
pp. 1362 ◽  
Author(s):  
Daijiro Yanagisawa ◽  
Nor Faeizah Ibrahim ◽  
Hiroyasu Taguchi ◽  
Shigehiro Morikawa ◽  
Takami Tomiyama ◽  
...  
Keyword(s):  
Magnetic Resonance Imaging ◽  
Magnetic Resonance ◽  
Amyloid Β ◽  
Resonance Imaging ◽  
Aβ Oligomers ◽  
Keto Form ◽  
19F Mri ◽  
The Brain ◽  
Curcumin Derivative

Recent evidence suggests that the formation of soluble amyloid β (Aβ) aggregates with high toxicity, such as oligomers and protofibrils, is a key event that causes Alzheimer’s disease (AD). However, understanding the pathophysiological role of such soluble Aβ aggregates in the brain in vivo could be difficult due to the lack of a clinically available method to detect, visualize, and quantify soluble Aβ aggregates in the brain. We had synthesized a novel fluorinated curcumin derivative with a fixed keto form, named as Shiga-Y51, which exhibited high selectivity to Aβ oligomers in vitro. In this study, we investigated the in vivo detection of Aβ oligomers by fluorine-19 (19F) magnetic resonance imaging (MRI) using Shiga-Y51 in an APP/PS1 double transgenic mouse model of AD. Significantly high levels of 19F signals were detected in the upper forebrain region of APP/PS1 mice compared with wild-type mice. Moreover, the highest levels of Aβ oligomers were detected in the upper forebrain region of APP/PS1 mice in enzyme-linked immunosorbent assay. These findings suggested that 19F-MRI using Shiga-Y51 detected Aβ oligomers in the in vivo brain. Therefore, 19F-MRI using Shiga-Y51 with a 7 T MR scanner could be a powerful tool for imaging Aβ oligomers in the brain.

scholarly journals Quinacrine directly dissociates amyloid plaques in the brain of 5XFAD transgenic mouse model of Alzheimer’s disease

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sohui Park ◽  
Hye Yun Kim ◽  
Hyun-A Oh ◽  
Jisu Shin ◽  
In Wook Park ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Weight ◽  
Transgenic Mice ◽  
Cortical Neurons ◽  
Amyloid Β ◽  
Synaptic Function ◽  
Western Blots ◽  
Aβ Fibrils ◽  
The Brain

AbstractAlzheimer’s disease (AD) is the most common type of dementia characterized by the abnormal accumulation of amyloid-β (Aβ) in the brain. Aβ misfolding is associated with neuroinflammation and synaptic dysfunction, leading to learning and memory deficits. Therefore, Aβ production and aggregation have been one of the most popular drug targets for AD. Failures of drug candidates regulating the aforementioned Aβ cascade stimulated development of immunotherapy agents for clearance of accumulated Aβ in the brain. Here, we report that quinacrine, a blood–brain barrier penetrating antimalarial chemical drug, dissociates Aβ plaques in the brain of AD transgenic mice. When co-incubated with pre-formed Aβ fibrils, quinacrine decreased thioflavin T-positive β-sheets in vitro, on top of its inhibitory function on the fibril formation. We confirmed that quinacrine induced dissociation of high-molecular-weight Aβ aggregates into low-molecular-weight species by dot blots in association with size cut-off filtrations. Quinacrine was then administered to adult 5XFAD transgenic mice via weekly intravenous injections for 6 weeks, and we found a significant reduction of Aβ plaques and astrocytosis in their cortex and hippocampus. In western blots of quinacrine-administered mouse brains, amelioration of AD-related biomarkers, glial fibrillary acidic protein, postsynaptic protein 95, phosphorylated cAMP response element-binding protein, phosphorylated c-Jun N-terminal kinase were observed. Lastly, quinacrine-stimulated dissociation of misfolded aggregates induced recovery of synaptic function associated with Aβ in excitatory post-synaptic current recordings of primary rat cortical neurons treated with Aβ aggregates and quinacrine. Collectively, quinacrine can directly dissociate Aβ fibrils and alleviate decreased synaptic functions.

scholarly journals Trichostatin A ameliorates Alzheimer’s disease-related pathology and cognitive deficits by increasing albumin expression and Aβ clearance in APP/PS1 mice

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Qiang Su ◽  
Tian Li ◽  
Pei-Feng He ◽  
Xue-Chun Lu ◽  
Qi Yu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Western Blotting ◽  
Molecular Mechanisms ◽  
Neurodegenerative Disorder ◽  
Trichostatin A ◽  
Amyloid Β ◽  
Aβ Oligomers ◽  
Aβ Clearance

Abstract Background Alzheimer’s disease (AD) is an intractable neurodegenerative disorder in the elderly population, currently lacking a cure. Trichostatin A (TSA), a histone deacetylase inhibitor, showed some neuroprotective roles, but its pathology-improvement effects in AD are still uncertain, and the underlying mechanisms remain to be elucidated. The present study aims to examine the anti-AD effects of TSA, particularly investigating its underlying cellular and molecular mechanisms. Methods Novel object recognition and Morris water maze tests were used to evaluate the memory-ameliorating effects of TSA in APP/PS1 transgenic mice. Immunofluorescence, Western blotting, Simoa assay, and transmission electron microscopy were utilized to examine the pathology-improvement effects of TSA. Microglial activity was assessed by Western blotting and transwell migration assay. Protein-protein interactions were analyzed by co-immunoprecipitation and LC-MS/MS. Results TSA treatment not only reduced amyloid β (Aβ) plaques and soluble Aβ oligomers in the brain, but also effectively improved learning and memory behaviors of APP/PS1 mice. In vitro study suggested that the improvement of Aβ pathology by TSA was attributed to the enhancement of Aβ clearance, mainly by the phagocytosis of microglia, and the endocytosis and transport of microvascular endothelial cells. Notably, a meaningful discovery in the study was that TSA dramatically upregulated the expression level of albumin in cell culture, by which TSA inhibited Aβ aggregation and promoted the phagocytosis of Aβ oligomers. Conclusions These findings provide a new insight into the pathogenesis of AD and suggest TSA as a novel promising candidate for the AD treatment.

scholarly journals Amphiphilic Distyrylbenzene Derivatives as Potential Therapeutic and Imaging Agents for the Soluble Amyloid-β Oligomers in Alzheimer’s Disease

2021 ◽  
Author(s):  
Liang Sun ◽  
Hong-Jun Cho ◽  
Soumyo Sen ◽  
Andres S. Arango ◽  
Truc T. Huynh ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Electrostatic Interactions ◽  
Amyloid Fibril ◽  
Amyloid Β ◽  
Amyloid Plaques ◽  
Aβ Peptide ◽  
Aβ Oligomers ◽  
5Xfad Mice ◽  
Soluble Aβ Oligomers

Alzheimer’s Diseases (AD) is the most common neurodegenerative disease, but efficient therapeutic and early diagnosis agents for this neurological disorder are still lacking. <a>Herein, we report the development of a novel amphiphilic compound, LS-4, generated linking a hydrophobic amyloid fibril-binding fragment with a hydrophilic azamacrocycle that can dramatically increase the binding affinity towards various amyloid β (Aβ) peptide aggregates. The developed compound exhibits uncommon fluorescence turn-on and high binding affinity for Aβ aggregates, especially for soluble Aβ oligomers. Moreover, upon the administration of LS-4 to 5xFAD mice, fluorescence imaging of the LS-4-treated brain sections reveals that LS-4 can readily penetrate the blood-brain-barrier (BBB) and bind to the Aβ oligomers <i>in vivo</i>, as confirmed by immunostaining with an Aβ oligomer-specific antibody. In addition, the treatment of 5xFAD mice with LS-4 significantly reduces the amount of both amyloid plaques and associated phosphorylated tau (p-tau) aggregates vs. the vehicle-treated 5xFAD mice, while microglia activation is also reduced. Furthermore, molecular dynamics simulations corroborate the observation that introducing a hydrophilic moiety into the molecular structure can significantly enhance the electrostatic interactions with the polar residues of the Aβ peptide species. Finally, taking advantage of the strong Cu-chelating property of the azamacrocycle, we performed a series of radioimaging and biodistribution studies that show the <sup>64</sup>Cu-LS-4 complex binds to the amyloid plaques and can accumulate a significantly larger extent in the 5xFAD mice brains vs. the WT controls. Overall, these <i>in vitro</i> and <i>in vivo</i> studies illustrate that the novel strategy to employ an amphiphilic molecule containing a hydrophilic fragment attached to a hydrophobic amyloid fibril-binding fragment </a><a>can increase the binding affinity of these compounds for the soluble Aβ oligomers and can thus be used </a>to detect and regulate the soluble Aβ species in AD.

scholarly journals Salivary Aβ Secretion and Altered Oral Microbiome in Mouse Models of AD

2021 ◽  
Vol 17 (12) ◽  
pp. 1133-1144
Author(s):  
Angela M. Floden ◽  
Mona Sohrabi ◽  
Suba Nookala ◽  
Jay J. Cao ◽  
Colin K. Combs
Keyword(s):  
Matched Control ◽  
Amyloid Β ◽  
Cell Types ◽  
Oral Microbiome ◽  
Aβ Peptide ◽  
Prior Work ◽  
Wild Type ◽  
Male And Female ◽  
Amyloid Aβ ◽  
The Brain

Background: Beta amyloid (Aβ) peptide containing plaque aggregations in the brain are a hallmark of Alzheimer’s Disease (AD). However, Aβ is produced by cell types outside of the brain suggesting that the peptide may serve a broad physiologic purpose. Objective: Based upon our prior work documenting expression of amyloid β precursor protein (APP) in intestinal epithelium we hypothesized that salivary epithelium might also express APP and be a source of Aβ. Methods: To begin testing this idea, we compared human age-matched control and AD salivary glands to C57BL/6 wild type, AppNL-G-F , and APP/PS1 mice. Results: Both male and female AD, AppNL-G-F , and APP/PS1 glands demonstrated robust APP and Aβ immunoreactivity. Female AppNL-G-F mice had significantly higher levels of pilocarpine stimulated Aβ 1-42 compared to both wild type and APP/PS1 mice. No differences in male salivary Aβ levels were detected. No significant differences in total pilocarpine stimulated saliva volumes were observed in any group. Both male and female AppNL-G-F but not APP/PS1 mice demonstrated significant differences in oral microbiome phylum and genus abundance compared to wild type mice. Male, but not female, APP/PS1 and AppNL-G-F mice had significantly thinner molar enamel compared to their wild type counterparts. Conclusion: These data support the idea that oral microbiome changes exist during AD in addition to changes in salivary Aβ and oral health.

scholarly journals Fluorescent indolizine derivative YI-13 detects amyloid-β monomers, dimers, and plaques in the brain of 5XFAD Alzheimer transgenic mouse model

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0243041
Author(s):  
DaWon Kim ◽  
Jeong Hwa Lee ◽  
Hye Yun Kim ◽  
Jisu Shin ◽  
Kyeonghwan Kim ◽  
...  
Keyword(s):  
Mouse Model ◽  
Transgenic Mouse ◽  
Neurodegenerative Disorder ◽  
Amyloid Β ◽  
Transgenic Mouse Model ◽  
Aβ Oligomers ◽  
Aβ Peptides ◽  
Soluble Aβ Oligomers ◽  
The Brain

Alzheimer disease (AD) is a neurodegenerative disorder characterized by the aberrant production and accumulation of amyloid-β (Aβ) peptides in the brain. Accumulated Aβ in soluble oligomer and insoluble plaque forms are considered to be a pathological culprit and biomarker of the disorder. Here, we report a fluorescent universal Aβ-indicator YI-13, 5-(4-fluorobenzoyl)-7,8-dihydropyrrolo[1,2-b]isoquinolin-9(6H)-one, which detects Aβ monomers, dimers, and plaques. We synthesized a library of 26 fluorescence chemicals with the indolizine core and screen them through a series of in vitro tests utilizing Aβ as a target and YI-13 was selected as the final imaging candidate. YI-13 was found to stain and visualize insoluble Aβ plaques in the brain tissue, of a transgenic mouse model with five familial AD mutations (5XFAD), by a histochemical approach and to label soluble Aβ oligomers within brain lysates of the mouse model under a fluorescence plate reader. Among oligomers aggregated from monomers and synthetic dimers from chemically conjugated monomers, YI-13 preferred the dimeric Aβ.

scholarly journals URMC-099 Prophylaxis Repairs Hippocampal Vascular Damage in an Orthopedic Model of Delirium Superimposed on Dementia

2021 ◽  
Author(s):  
Patrick Miller-Rhodes ◽  
Herman Li ◽  
Ravikanth Velagapudi ◽  
Niccolo Terrando ◽  
Harris A Gelbard
Keyword(s):  
Cognitive Deficits ◽  
Microglial Activation ◽  
Molecular Mechanisms ◽  
Amyloid Β ◽  
Endothelial Activation ◽  
Surgical Trauma ◽  
Data Link ◽  
Synapse Loss ◽  
The Brain ◽  
Delirium Superimposed On Dementia

Systemic perturbations can drive a neuroimmune cascade after surgical trauma, including affecting the blood-brain barrier (BBB), activating microglia, and contributing to cognitive deficits such as delirium. Delirium superimposed on dementia (DSD) is a particularly debilitating complication that renders the brain further vulnerable to neuroinflammation and neurodegeneration, albeit these molecular mechanisms remain poorly understood. Here we have used an orthopedic model of tibial fracture/fixation in APPSwDI/mNos2-/- AD (CVN-AD) mice to investigate relevant pathogenetic mechanisms underlying DSD. We conducted the present study in 6 months-old CVN-AD mice, an age at which we speculated amyloid-β pathology had not saturated BBB and neuroimmune functioning. We found that URMC-099, our brain-penetrant anti-inflammatory neuroprotective drug, prevented inflammatory endothelial activation, synapse loss, and microglial activation in our DSD model. Taken together, our data link post-surgical endothelial activation, microglial MafB immunoreactivity, and synapse loss as key substrates for DSD, all of which can be reversed by URMC-099.

scholarly journals Impairments of neural circuit function in Alzheimer's disease

2016 ◽  
Vol 371 (1700) ◽  
pp. 20150429 ◽  
Author(s):  
Marc Aurel Busche ◽  
Arthur Konnerth
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Hippocampal Neurons ◽  
Large Scale ◽  
Neural Circuit ◽  
Essential Feature ◽  
Amyloid Β ◽  
Amyloid Plaque ◽  
Aβ Oligomers ◽  
The Brain

An essential feature of Alzheimer's disease (AD) is the accumulation of amyloid-β (Aβ) peptides in the brain, many years to decades before the onset of overt cognitive symptoms. We suggest that during this very extended early phase of the disease, soluble Aβ oligomers and amyloid plaques alter the function of local neuronal circuits and large-scale networks by disrupting the balance of synaptic excitation and inhibition ( E / I balance) in the brain. The analysis of mouse models of AD revealed that an Aβ-induced change of the E / I balance caused hyperactivity in cortical and hippocampal neurons, a breakdown of slow-wave oscillations, as well as network hypersynchrony. Remarkably, hyperactivity of hippocampal neurons precedes amyloid plaque formation, suggesting that hyperactivity is one of the earliest dysfunctions in the pathophysiological cascade initiated by abnormal Aβ accumulation. Therapeutics that correct the E / I balance in early AD may prevent neuronal dysfunction, widespread cell loss and cognitive impairments associated with later stages of the disease. This article is part of the themed issue ‘Evolution brings Ca 2+ and ATP together to control life and death’.

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