P3-208: Isoform specific effects of ApoE4 on the formation of soluble Aβ oligomers in vivo

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 in vivo, 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 64Cu-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 in vitro and in vivo 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.

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The Role of Polyphenols in the Treatment of Alzheimer's Disease: Narrative Review

Al-Rafidain Journal of Medical Sciences ( ISSN: 2789-3219 ) ◽

10.54133/ajms.v1i.31 ◽

2021 ◽

Vol 1 ◽

pp. 53-61

Author(s):

Reem Halim Alattiya ◽

Farah Khalid Tarish ◽

Lina Loai Hashim ◽

Saad Abdulrahman Hussain

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Epidemiological Studies ◽

Aβ Oligomers ◽

In Vivo Models ◽

Natural Polyphenols ◽

Disease Modifying Agents ◽

Soluble Aβ Oligomers

Many epidemiological studies have suggested that consuming a diet rich in polyphenols can help prevent Alzheimer's disease (AD). Based on well-known in vitro and in vivo models of cerebral Aβ amyloidosis, we examined the data on the effects of various natural polyphenols on the aggregation of amyloid-protein (Aβ). These polyphenols effectively prevent oligomerization and fibril formation of Aβ through differential binding patterns, lowering Aβ oligomer-induced synaptic and neuronal toxicity, according to in vitro investigations. Furthermore, in a transgenic mouse model fed orally with such polyphenolic compounds, soluble Aβ oligomers as well as insoluble Aβ deposits in the brain were significantly reduced. Natural polyphenols exhibit anti-amyloidogenic effects on Aβ, in addition to well-known anti-oxidative and anti-inflammatory activities, according to an updated assessment of the literature, implying their potential as therapeutic and/or preventive agents for AD treatment. To prove polyphenols' efficacy as disease-modifying agents, well-designed clinical trials or preventive treatments using various polyphenols are required.

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Soluble Aβ Oligomers Are Rapidly Sequestered from Brain ISF In Vivo and Bind GM1 Ganglioside on Cellular Membranes

Neuron ◽

10.1016/j.neuron.2014.02.027 ◽

2014 ◽

Vol 82 (2) ◽

pp. 308-319 ◽

Cited By ~ 106

Author(s):

Soyon Hong ◽

Beth L. Ostaszewski ◽

Ting Yang ◽

Tiernan T. O’Malley ◽

Ming Jin ◽

...

Keyword(s):

Gm1 Ganglioside ◽

Cellular Membranes ◽

Aβ Oligomers ◽

Soluble Aβ Oligomers

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

10.26434/chemrxiv.13605998 ◽

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 in vivo, 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 64Cu-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 in vitro and in vivo 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.

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METTL3-dependent RNA m6A dysregulation contributes to neurodegeneration in Alzheimer’s disease through aberrant cell cycle events

Molecular Neurodegeneration ◽

10.1186/s13024-021-00484-x ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Fanpeng Zhao ◽

Ying Xu ◽

Shichao Gao ◽

Lixia Qin ◽

Quillan Austria ◽

...

Keyword(s):

Oxidative Stress ◽

Cell Cycle ◽

Neuronal Damage ◽

Underlying Mechanism ◽

Aβ Oligomers ◽

Aberrant Cell ◽

Soluble Aβ Oligomers ◽

The Impact

Abstract Background N6-methyladenosine (m6A) modification of RNA influences fundamental aspects of RNA metabolism and m6A dysregulation is implicated in various human diseases. In this study, we explored the potential role of RNA m6A modification in the pathogenesis of Alzheimer disease (AD). Methods We investigated the m6A modification and the expression of m6A regulators in the brain tissues of AD patients and determined the impact and underlying mechanism of manipulated expression of m6A levels on AD-related deficits both in vitro and in vivo. Results We found decreased neuronal m6A levels along with significantly reduced expression of m6A methyltransferase like 3 (METTL3) in AD brains. Interestingly, reduced neuronal m6A modification in the hippocampus caused by METTL3 knockdown led to significant memory deficits, accompanied by extensive synaptic loss and neuronal death along with multiple AD-related cellular alterations including oxidative stress and aberrant cell cycle events in vivo. Inhibition of oxidative stress or cell cycle alleviated shMettl3-induced apoptotic activation and neuronal damage in primary neurons. Restored m6A modification by inhibiting its demethylation in vitro rescued abnormal cell cycle events, neuronal deficits and death induced by METTL3 knockdown. Soluble Aβ oligomers caused reduced METTL3 expression and METTL3 knockdown exacerbated while METTL3 overexpression rescued Aβ-induced synaptic PSD95 loss in vitro. Importantly, METTL3 overexpression rescued Aβ-induced synaptic damage and cognitive impairment in vivo. Conclusions Collectively, these data suggested that METTL3 reduction-mediated m6A dysregulation likely contributes to neurodegeneration in AD which may be a therapeutic target for AD.

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Anti-Parallel β-Hairpin Structure in Soluble Aβ Oligomers of Aβ40-Dutch and Aβ40-Iowa

International Journal of Molecular Sciences ◽

10.3390/ijms22031225 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1225

Author(s):

Ziao Fu ◽

William E. Van Nostrand ◽

Steven O. Smith

Keyword(s):

Amyloid Β ◽

Amyloid Angiopathy ◽

Aβ Oligomers ◽

Dominant Component ◽

Fibril Structure ◽

Predominant Component ◽

Aβ Aggregation ◽

Aβ Fibrils ◽

Soluble Aβ Oligomers ◽

Β Sheet

The amyloid-β (Aβ) peptides are associated with two prominent diseases in the brain, Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA). Aβ42 is the dominant component of cored parenchymal plaques associated with AD, while Aβ40 is the predominant component of vascular amyloid associated with CAA. There are familial CAA mutations at positions Glu22 and Asp23 that lead to aggressive Aβ aggregation, drive vascular amyloid deposition and result in degradation of vascular membranes. In this study, we compared the transition of the monomeric Aβ40-WT peptide into soluble oligomers and fibrils with the corresponding transitions of the Aβ40-Dutch (E22Q), Aβ40-Iowa (D23N) and Aβ40-Dutch, Iowa (E22Q, D23N) mutants. FTIR measurements show that in a fashion similar to Aβ40-WT, the familial CAA mutants form transient intermediates with anti-parallel β-structure. This structure appears before the formation of cross-β-sheet fibrils as determined by thioflavin T fluorescence and circular dichroism spectroscopy and occurs when AFM images reveal the presence of soluble oligomers and protofibrils. Although the anti-parallel β-hairpin is a common intermediate on the pathway to Aβ fibrils for the four peptides studied, the rate of conversion to cross-β-sheet fibril structure differs for each.

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Neurotoxic Soluble Amyloid Oligomers Drive Alzheimer’s Pathogenesis and Represent a Clinically Validated Target for Slowing Disease Progression

International Journal of Molecular Sciences ◽

10.3390/ijms22126355 ◽

2021 ◽

Vol 22 (12) ◽

pp. 6355

Author(s):

Martin Tolar ◽

John Hey ◽

Aidan Power ◽

Susan Abushakra

Keyword(s):

Disease Progression ◽

Late Stage ◽

Large Body ◽

Amyloid Plaque ◽

Distinct Species ◽

Clinical Effects ◽

Aβ Oligomers ◽

Amyloid Toxicity ◽

Sequence Of Events ◽

Soluble Aβ Oligomers

A large body of clinical and nonclinical evidence supports the role of neurotoxic soluble beta amyloid (amyloid, Aβ) oligomers as upstream pathogenic drivers of Alzheimer’s disease (AD). Recent late-stage trials in AD that have evaluated agents targeting distinct species of Aβ provide compelling evidence that inhibition of Aβ oligomer toxicity represents an effective approach to slow or stop disease progression: (1) only agents that target soluble Aβ oligomers show clinical efficacy in AD patients; (2) clearance of amyloid plaque does not correlate with clinical improvements; (3) agents that predominantly target amyloid monomers or plaque failed to show clinical effects; and (4) in positive trials, efficacy is greater in carriers of the ε4 allele of apolipoprotein E (APOE4), who are known to have higher brain concentrations of Aβ oligomers. These trials also show that inhibiting Aβ neurotoxicity leads to a reduction in tau pathology, suggesting a pathogenic sequence of events where amyloid toxicity drives an increase in tau formation and deposition. The late-stage agents with positive clinical or biomarker data include four antibodies that engage Aβ oligomers (aducanumab, lecanemab, gantenerumab, and donanemab) and ALZ-801, an oral agent that fully blocks the formation of Aβ oligomers at the clinical dose.

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Analysis of anticoagulants for blood-based quantitation of amyloid β oligomers in the sFIDA assay

Biological Chemistry ◽

10.1515/hsz-2016-0153 ◽

2017 ◽

Vol 398 (4) ◽

pp. 465-475 ◽

Cited By ~ 4

Author(s):

Kateryna Kravchenko ◽

Andreas Kulawik ◽

Maren Hülsemann ◽

Katja Kühbach ◽

Christian Zafiu ◽

...

Keyword(s):

Blood Plasma ◽

Limit Of Detection ◽

Amyloid Β ◽

Distribution Analysis ◽

Aβ Oligomers ◽

Quantitative Measurements ◽

Suitable Parameter ◽

Edta Plasma ◽

Soluble Aβ Oligomers ◽

Parameter Values

Abstract Early diagnostics at the preclinical stage of Alzheimer’s disease is of utmost importance for drug development in clinical trials and prognostic guidance. Since soluble Aβ oligomers are considered to play a crucial role in the disease pathogenesis, several methods aim to quantify Aβ oligomers in body fluids such as cerebrospinal fluid (CSF) and blood plasma. The highly specific and sensitive method surface-based fluorescence intensity distribution analysis (sFIDA) has successfully been established for oligomer quantitation in CSF samples. In our study, we explored the sFIDA method for quantitative measurements of synthetic Aβ particles in blood plasma. For this purpose, EDTA-, citrate- and heparin-treated blood plasma samples from five individual donors were spiked with Aβ coated silica nanoparticles (Aβ-SiNaPs) and were applied to the sFIDA assay. Based on the assay parameters linearity, coefficient of variation and limit of detection, we found that EDTA plasma yields the most suitable parameter values for quantitation of Aβ oligomers in sFIDA assay with a limit of detection of 16 fM.

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Substrate-Specific Effects of Natural Genetic Variation on Proteasome Activity

10.1101/2021.11.23.469794 ◽

2021 ◽

Author(s):

Mahlon Collins ◽

Randi R. Avery ◽

Frank W Albert

Keyword(s):

Genetic Variation ◽

Protein Degradation ◽

Dynamic Control ◽

Cellular Protein ◽

Proteasome Activity ◽

Heritable Variation ◽

Natural Genetic Variation ◽

Specific Effects ◽

Regulatory Particle

The bulk of targeted cellular protein degradation is performed by the proteasome, a multi-subunit complex consisting of the 19S regulatory particle, which binds, unfolds, and translocates substrate proteins, and the 20S core particle, which degrades them. Protein homeostasis requires precise, dynamic control of proteasome activity. To what extent genetic variation creates differences in proteasome activity is almost entirely unknown. Using the ubiquitin-independent degrons of the ornithine decarboxylase and Rpn4 proteins, we developed reporters that provide high-throughput, quantitative measurements of proteasome activity in vivo in genetically diverse cell populations. We used these reporters to characterize the genetic basis of variation in proteasome activity in the yeast Saccharomyces cerevisiae. We found that proteasome activity is a complex, polygenic trait, shaped by variation throughout the genome. Genetic influences on proteasome activity were predominantly substrate-specific, suggesting that they primarily affect the function or activity of the 19S regulatory particle. Our results demonstrate that individual genetic differences create heritable variation in proteasome activity and suggest that genetic effects on proteasomal protein degradation may be an important source of variation in cellular and organismal traits.

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Antitumoral and Anti-inflammatory Roles of Somatostatin and Its Analogs in Hepatocellular Carcinoma

Analytical Cellular Pathology ◽

10.1155/2021/1840069 ◽

2021 ◽

Vol 2021 ◽

pp. 1-13

Author(s):

Argyrios Periferakis ◽

Georgios Tsigas ◽

Aristodemos-Theodoros Periferakis ◽

Ioana Anca Badarau ◽

Andreea-Elena Scheau ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Clinical Trials ◽

Primary Liver Cancer ◽

Somatostatin Receptors ◽

Metastatic Potential ◽

Cancer Staging ◽

Complete Evaluation ◽

Specific Effects

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and affects about 8% of cirrhotic patients, with a recurrence rate of over 50%. There are numerous therapies available for the treatment of HCC, depending on cancer staging and condition of the patient. The complexity of the treatment is also justified by the unique pathogenesis of HCC that involves intricate processes such as chronic inflammation, fibrosis, and multiple molecular carcinogenesis events. During the last three decades, multiple in vivo and in vitro experiments have used somatostatin and its analogs (SSAs) to reduce the proliferative and metastatic potential of hepatoma cells by inducing their apoptosis and reducing angiogenesis and the inflammatory component of HCC. Most experiments have proven successful, revealing several different pathways and mechanisms corresponding to the aforementioned functions. Moreover, a correlation between specific effects and expression of somatostatin receptors (SSTRs) was observed in the studied cells. Clinical trials have tested either somatostatin or an analog, alone or in combination with other drugs, to explore the potential effects on HCC patients, in various stages of the disease. While the majority of these clinical trials exhibited minor to moderate success, some other studies were inconclusive or even reported negative outcomes. A complete evaluation of the efficacy of somatostatin and SSAs is still the matter of intense debate, and, if deemed useful, these substances may play a beneficial role in the management of HCC patients.

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