Different Fates of Alzheimer’s Disease Amyloid-β Fibrils Remodeled by Biocompatible Small Molecules

2012 ◽  
Vol 14 (1) ◽  
pp. 264-274 ◽  
Author(s):  
Jacob A. Irwin ◽  
H. Edward Wong ◽  
Inchan Kwon
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Small Molecules ◽  
Amyloid Β

scholarly journals Modulatory Effects of Autophagy on APP Processing as a Potential Treatment Target for Alzheimer’s Disease

Biomedicines ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 5
Author(s):  
Md. Ataur Rahman ◽  
Md Saidur Rahman ◽  
MD. Hasanur Rahman ◽  
Mohammad Rasheduzzaman ◽  
ANM Mamun-Or-Rashid ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Small Molecules ◽  
Early Stage ◽  
Pathological Condition ◽  
Critical Role ◽  
Amyloid Β ◽  
Treatment Target ◽  
App Processing ◽  
Phosphorylated Tau Protein

Alzheimer’s disease (AD) is characterized by the formation of intracellular aggregate composed of heavily phosphorylated tau protein and extracellular deposit of amyloid-β (Aβ) plaques derived from proteolysis cleavage of amyloid precursor protein (APP). Autophagy refers to the lysosomal-mediated degradation of cytoplasmic constituents, which plays a critical role in maintaining cellular homeostasis. Importantly, recent studies reported that dysregulation of autophagy is associated in the pathogenesis of AD, and therefore, autophagy modulation has gained attention as a promising approach to treat AD pathogenesis. In AD, both the maturation of autolysosomes and its retrograde transports have been obstructed, which causes the accumulation of autophagic vacuoles and eventually leads to degenerating and dystrophic neurites function. However, the mechanism of autophagy modulation in APP processing and its pathogenesis have not yet been fully elucidated in AD. In the early stage of AD, APP processing and Aβ accumulation-mediated autophagy facilitate the removal of toxic protein aggregates via mTOR-dependent and -independent pathways. In addition, a number of autophagy-related genes (Atg) and APP are thought to influence the development of AD, providing a bidirectional link between autophagy and AD pathology. In this review, we summarized the current observations related to autophagy regulation and APP processing in AD, focusing on their modulation associated with the AD progression. Moreover, we emphasizes the application of small molecules and natural compounds to modulate autophagy for the removal and clearance of APP and Aβ deposits in the pathological condition of AD.

scholarly journals Small-Molecule Amyloid Beta-Aggregation Inhibitors in Alzheimer's Disease Drug Development

2019 ◽  
Vol 01 (01) ◽  
pp. e22-e32
Author(s):  
Sharmin Reza Chowdhury ◽  
Fangzhou Xie ◽  
Jinxin Gu ◽  
Lei Fu
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Small Molecules ◽  
Small Molecule ◽  
Disease Process ◽  
Amyloid Β ◽  
Symptomatic Improvement ◽  
Starting Point ◽  
Aβ Aggregation ◽  
Aggregation Inhibitors

AbstractAlzheimer's disease (AD) is still an incurable neurodegenerative disease that causes dementia. AD changes the brain function that, over time, impairs memory and diminishes judgment and reasoning ability. Pathophysiology of AD is complex. Till now the cause of AD remains unknown, but risk factors include family history and genetic predisposition. The drugs previously approved for AD treatment do not modify the disease process and only provide symptomatic improvement. Over the past few decades, research has led to significant progress in the understanding of the disease, leading to several novel strategies that may modify the disease process. One of the major developments in this direction is the amyloid β (Aβ) aggregation. Small molecules could block the initial stages of Aβ aggregation, which could be the starting point for the design and development of new AD drugs in the near future. In this review we summarize the most promising small-molecule Aβ-aggregation inhibitors including natural compounds, novel small molecules, and also those are in clinical trials. Moreover, we briefly summarized some reported docking studies of small-molecule Aβ aggregation inhibitors. These will give us an idea about the chemical features required to design novel small molecules with anti-Aβ aggregation properties.

scholarly journals High Throughput Screening at the Membrane Interface Reveals New Inhibitors of Amyloid-β

2019 ◽  
Author(s):  
Sarah J. Cox ◽  
Brian Lam ◽  
Ajay Prasad ◽  
Hannah A. Marietta ◽  
Nicholas V. Stander ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Membrane ◽  
Small Molecules ◽  
High Throughput ◽  
High Throughput Screening ◽  
Amyloid Β ◽  
Amyloid Aggregation ◽  
Membrane Interface

Amyloid-β aggregation at the cell-membrane of neruonal cells is implicated as a source of toxicity for Alzheimer’s disease. Small molecules have been studied for their ability to supress amyloid aggregation and toxicity, but the presence of membranes negate their activity. Here, we have identified 5 small molecules that are active at the membrane interface.

scholarly journals Protection against Amyloid-β Oligomer Neurotoxicity by Small Molecules with Antioxidative Properties: Potential for the Prevention of Alzheimer’s Disease Dementia

Antioxidants ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 132
Author(s):  
Wataru Araki ◽  
Fuyuki Kametani
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Small Molecules ◽  
Critical Role ◽  
Amyloid Β ◽  
Amyloid Β Protein ◽  
Aβ Oligomers ◽  
Antioxidative Properties ◽  
Drug Candidates ◽  
Β Protein

Soluble oligomeric assemblies of amyloid β-protein (Aβ), called Aβ oligomers (AβOs), have been recognized as primary pathogenetic factors in the molecular pathology of Alzheimer’s disease (AD). AβOs exert neurotoxicity and synaptotoxicity and play a critical role in the pathological progression of AD by aggravating oxidative and synaptic disturbances and tau abnormalities. As such, they are important therapeutic targets. From a therapeutic standpoint, it is not only important to clear AβOs or prevent their formation, it is also beneficial to reduce their neurotoxicity. In this regard, recent studies have reported that small molecules, most with antioxidative properties, show promise as therapeutic agents for reducing the neurotoxicity of AβOs. In this mini-review, we briefly review the significance of AβOs and oxidative stress in AD and summarize studies on small molecules with AβO-neurotoxicity-reducing effects. We also discuss mechanisms underlying the effects of these compounds against AβO neurotoxicity as well as their potential as drug candidates for the prevention and treatment of AD.

ANTI-TAU TRIALS FOR ALZHEIMER’S DISEASE: A REPORT FROM THE EU/US/CTAD TASK FORCE

2019 ◽  
pp. 1-7
Author(s):  
J. Cummings ◽  
K. Blennow ◽  
K. Johnson ◽  
M. Keeley ◽  
R.J. Bateman ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Small Molecules ◽  
Task Force ◽  
Phase 1 ◽  
Amyloid Β ◽  
Imaging Studies ◽  
And Function ◽  
The Brain ◽  
The Eu

Efforts to develop effective disease-modifying treatments for Alzheimer’s disease (AD) have mostly targeted the amyloid β (Aβ) protein; however, there has recently been increased interest in other targets including phosphorylated tau and other forms of tau. Aggregated tau appears to spread in a characteristic pattern throughout the brain and is thought to drive neurodegeneration. Both neuropathological and imaging studies indicate that tau first appears in the entorhinal cortex and then spreads to the neocortex. Anti-tau therapies currently in Phase 1 or 2 trials include passive and active immunotherapies designed to prevent aggregation, seeding, and spreading, as well as small molecules that modulate tau metabolism and function. EU/US/CTAD Task Force members support advancing the development of anti-tau therapies, which will require novel imaging agents and biomarkers, a deeper understanding of tau biology and the dynamic interaction of tau and Aβ protein, and development of multiple targets and candidate agents addressing the tauopathy of AD. Incorporating tau biomarkers in AD clinical trials will provide additional knowledge about the potential to treat AD by targeting tau.

scholarly journals Systematic development of small molecules to inhibit specific microscopic steps of Aβ42 aggregation in Alzheimer’s disease

2016 ◽  
Vol 114 (2) ◽  
pp. E200-E208 ◽  
Author(s):  
Johnny Habchi ◽  
Sean Chia ◽  
Ryan Limbocker ◽  
Benedetta Mannini ◽  
Minkoo Ahn ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Drug Discovery ◽  
Small Molecules ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Lead Compounds ◽  
Rational Drug ◽  
Powerful Approach ◽  
Systematic Development

The aggregation of the 42-residue form of the amyloid-β peptide (Aβ42) is a pivotal event in Alzheimer’s disease (AD). The use of chemical kinetics has recently enabled highly accurate quantifications of the effects of small molecules on specific microscopic steps in Aβ42 aggregation. Here, we exploit this approach to develop a rational drug discovery strategy against Aβ42 aggregation that uses as a read-out the changes in the nucleation and elongation rate constants caused by candidate small molecules. We thus identify a pool of compounds that target specific microscopic steps in Aβ42 aggregation. We then test further these small molecules in human cerebrospinal fluid and in a Caenorhabditis elegans model of AD. Our results show that this strategy represents a powerful approach to identify systematically small molecule lead compounds, thus offering an appealing opportunity to reduce the attrition problem in drug discovery.

The Ongoing Search for Small Molecules to Study Metal-Associated Amyloid-β Species in Alzheimer’s Disease

2014 ◽  
Vol 47 (8) ◽  
pp. 2475-2482 ◽  
Author(s):  
Masha G. Savelieff ◽  
Alaina S. DeToma ◽  
Jeffrey S. Derrick ◽  
Mi Hee Lim
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Small Molecules ◽  
Amyloid Β

Amyloid β-peptide and Alzheimer's disease

2014 ◽  
Vol 56 ◽  
pp. 99-110 ◽  
Author(s):  
David Allsop ◽  
Jennifer Mayes
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Senile Plaques ◽  
Strong Support ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Amyloid Cascade Hypothesis ◽  
Sequence Of Events ◽  
Aβ Amyloid ◽  
Amyloid Cascade

One of the hallmarks of AD (Alzheimer's disease) is the formation of senile plaques in the brain, which contain fibrils composed of Aβ (amyloid β-peptide). According to the ‘amyloid cascade’ hypothesis, the aggregation of Aβ initiates a sequence of events leading to the formation of neurofibrillary tangles, neurodegeneration, and on to the main symptom of dementia. However, emphasis has now shifted away from fibrillar forms of Aβ and towards smaller and more soluble ‘oligomers’ as the main culprit in AD. The present chapter commences with a brief introduction to the disease and its current treatment, and then focuses on the formation of Aβ from the APP (amyloid precursor protein), the genetics of early-onset AD, which has provided strong support for the amyloid cascade hypothesis, and then on the development of new drugs aimed at reducing the load of cerebral Aβ, which is still the main hope for providing a more effective treatment for AD in the future.

Minimalistic Design Approach for Multi-Reactivity against Free Radicals and Metal-Free and Metal-Bound Amyloid-β Peptides: Redox-Based Substitutions of Benzene

2019 ◽  
Author(s):  
Mingeun Kim ◽  
Juhye Kang ◽  
Misun Lee ◽  
Jiyeon Han ◽  
Geewoo Nam ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Free Radicals ◽  
Amyloid Β ◽  
Design Strategy ◽  
Design Approach ◽  
Metal Free

We report a minimalistic redox-based design strategy for engineering compact molecules based on the simplest aromatic framework, benzene, with multi-reactivity against free radicals, metal-free amyloid-β, and metal-bound amyloid-β, implicated in the most common form of dementia, Alzheimer’s disease.

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