Abstract
Amyloid β-derived diffusible ligands (ADDLs) comprise the neurotoxic subset of soluble Aβ1-42 oligomers, now widely considered to be the molecular cause of memory malfunction and neurodegeneration in Alzheimers disease (AD). We have developed a screening cascade which identifies small molecule modulators of ADDL-mediated neurotoxicity. The primary screen involves a fluorescence resonance energy transfer (FRET)-based assay which selects inhibitors of Aβ1-42 oligomer assembly. The identified hits were further characterized by assessing their ability to inhibit the assembly and binding of ADDLs to cultures of primary hippocampal neurons. This approach has led to the identification of a number of small molecules which inhibit ADDL assembly and their subsequent binding to neurons. Here we describe our small molecule discovery efforts to identify ADDL assembly blocker and ADDL binding inhibitors, and to transform validated hits into pre-clinical lead compounds.
Keywords: ADDL, Alzheimer, amyloid, assembly, drug, inhibitor, neuron, oligomer
Current Alzheimer Research
Title: Discovery of ADDL-Targeting Small Molecule Drugs for Alzheimers Disease
Volume: 4 Issue: 5
Author(s): Raymond M. Lowe, Grant A. Krafft, David Summa, William F. Goure, Susan M. Catalano, Sue Zhang, Hsiu-Mei Wu, Lily Ruslim-Litrus, Michele McEntee, Gary C. Look, Catherine M. Hironaka, Lev Igoudin, Walter J. Crosier, Jean-Claude R. Breach, Todd R. Pray, Diana B. Cherbavaz and Jasna Jerecic
Affiliation:
Keywords: ADDL, Alzheimer, amyloid, assembly, drug, inhibitor, neuron, oligomer
Abstract: Amyloid β-derived diffusible ligands (ADDLs) comprise the neurotoxic subset of soluble Aβ1-42 oligomers, now widely considered to be the molecular cause of memory malfunction and neurodegeneration in Alzheimers disease (AD). We have developed a screening cascade which identifies small molecule modulators of ADDL-mediated neurotoxicity. The primary screen involves a fluorescence resonance energy transfer (FRET)-based assay which selects inhibitors of Aβ1-42 oligomer assembly. The identified hits were further characterized by assessing their ability to inhibit the assembly and binding of ADDLs to cultures of primary hippocampal neurons. This approach has led to the identification of a number of small molecules which inhibit ADDL assembly and their subsequent binding to neurons. Here we describe our small molecule discovery efforts to identify ADDL assembly blocker and ADDL binding inhibitors, and to transform validated hits into pre-clinical lead compounds.
Export Options
About this article
Cite this article as:
Lowe M. Raymond, Krafft A. Grant, Summa David, Goure F. William, Catalano M. Susan, Zhang Sue, Wu Hsiu-Mei, Ruslim-Litrus Lily, McEntee Michele, Look C. Gary, Hironaka M. Catherine, Igoudin Lev, Crosier J. Walter, Breach R. Jean-Claude, Pray R. Todd, Cherbavaz B. Diana and Jerecic Jasna, Discovery of ADDL-Targeting Small Molecule Drugs for Alzheimers Disease, Current Alzheimer Research 2007; 4 (5) . https://dx.doi.org/10.2174/156720507783018271
DOI https://dx.doi.org/10.2174/156720507783018271 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
Call for Papers in Thematic Issues
New Advances in the Prevention, Diagnosis, Treatment, and Rehabilitation of Alzheimer's Disease
Aims and Scope: Introduction: Alzheimer's disease (AD) poses a significant global health challenge, with an increasing prevalence that demands concerted efforts to advance our understanding and strategies for prevention, diagnosis, treatment, and rehabilitation. This thematic issue aims to bring together cutting-edge research and innovative approaches from multidisciplinary perspectives to address ...read more
Current updates on the Role of Neuroinflammation in Neurodegenerative Disorders
Neuroinflammation is an invariable hallmark of chronic and acute neurodegenerative disorders and has long been considered a potential drug target for Alzheimer?s disease (AD) and dementia. Significant evidence of inflammatory processes as a feature of AD is provided by the presence of inflammatory markers in plasma, CSF and postmortem brain ...read more
Deep Learning for Advancing Alzheimer's Disease Research
Alzheimer's disease (AD) poses a significant global health challenge, with an increasing number of individuals affected yearly. Deep learning, a subfield of artificial intelligence, has shown immense potential in various domains, including healthcare. This thematic issue of Current Alzheimer Research explores the application of deep learning techniques in advancing our ...read more
Diagnostic and therapeutic biomarkers of dementia
Dementia affects 18 million people worldwide. Dementia is a syndrome of symptoms caused by brain disease, usually chronic or progressive, clinically characterized by multiple impairments of higher cortical functions such as memory, thinking, orientation, and learning. In addition, in the course of dementia, cognitive deficits are observed, which often hinder ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Polyphenols: A Diverse Class of Multi-Target Anti-HIV-1 Agents
Current Drug Metabolism Phenylbutyric Acid: Simple Structure - Multiple Effects
Current Pharmaceutical Design Peptide-Mediated Cellular Delivery of Oligonucleotide-Based Therapeutics In Vitro: Quantitative Evaluation of Overall Efficacy Employing Easy to Handle Reporter Systems
Current Pharmaceutical Design Effects of Music Therapy on Psychological Symptoms and Heart Rate Variability in Patients with Dementia. A Pilot Study
Current Aging Science Relevance of the Vascular Effects of Insulin in the Rationale of its Therapeutical Use
Cardiovascular & Hematological Disorders-Drug Targets Anti-platelet Drug-loaded Targeted Technologies for the Effective Treatment of Atherothrombosis
Current Drug Targets Treating the Cognitive Deficits of Schizophrenia with Alpha4Beta2 Neuronal Nicotinic Receptor Agonists
Current Pharmaceutical Design Hydrogen Sulfide: A New Tool to Design and Develop Drugs
Clinical Anti-Inflammatory & Anti-Allergy Drugs (Discontinued) Markers of Systemic Inflammation in Obstructive Sleep Apnea Syndrome
Current Respiratory Medicine Reviews Novel Systemic Markers for Patients with Alzheimer Disease? – A Pilot Study
Current Alzheimer Research Potential New Targets for Antithrombotic Therapy
Current Pharmaceutical Design Second-Generation Antipsychotic Agents: A Review of Safety Profiles
Current Psychiatry Reviews Clinical Relevance of Apolipoprotein E Genotyping Based on a Family History of Alzheimer's Disease
Current Alzheimer Research Subject Index to Volume 4
Current Medicinal Chemistry - Central Nervous System Agents Transient Receptor Potential (TRP) Cation Channels in Diabetes
Current Topics in Medicinal Chemistry The “Invisible Proteome”: How to Capture the Low-Abundance Proteins Via Combinatorial Ligand Libraries
Current Proteomics Serum Albumin Concentration and Cognitive Impairment
Current Alzheimer Research Bedtime Hypertension Chronotherapy: Concepts and Patient Outcomes
Current Pharmaceutical Design Dolichol: A Natural Biomarker of Aging Endowed With a Photoenhanced Highly-Effective Solar Filter Activity
Recent Patents on Endocrine, Metabolic & Immune Drug Discovery Tau, Amyloid Beta and Deep Brain Stimulation: Aiming to Restore Cognitive Deficit in Alzheimer's Disease
Current Alzheimer Research