• Amyloid fibril
• Hydrophobic interaction
• Inhibition
• Lysozyme
• Metal polyphenolic network
• Protein aggregation
• Silver nanoparticle

• Muramidase/chemistry
• Muramidase/metabolism
• Silver/chemistry
• Silver/pharmacology
• Metal Nanoparticles/chemistry
• Polyphenols/pharmacology
• Polyphenols/chemistry
• Amyloid/chemistry
• Amyloid/metabolism
• Amyloid/antagonists & inhibitors
• Animals
• Chickens
• Kinetics
• Protein Aggregates/drug effects

• Institute for Advanced Studies in Basic Sciences
• Iran National Science Foundation

• Lysozyme amyloids
• Nanomaterials
• Phytotherapeutics
• Protein aggregation
• Protein phase transition

• Muramidase/chemistry
• Muramidase/metabolism
• Amyloid/chemistry
• Amyloid/metabolism
• Amyloid/antagonists & inhibitors
• Humans
• Nanostructures/chemistry
• Phase Transition
• Animals
• Amyloidosis/metabolism
• Amyloidosis/pathology
• Amyloidosis/drug therapy

• 2,4 Dinitrophenol
• In vitro model of Alzheimer's disease
• Mitochondria
• Neuroprotection
• Oxidative stress
• Tau pathology

• Alzheimer Disease/metabolism
• Alzheimer Disease/drug therapy
• Alzheimer Disease/pathology
• Okadaic Acid/pharmacology
• Okadaic Acid/toxicity
• Humans
• 2,4-Dinitrophenol/pharmacology
• Mitochondria/metabolism
• Mitochondria/drug effects
• Reactive Oxygen Species/metabolism
• Cell Line, Tumor
• Cell Survival/drug effects
• tau Proteins/metabolism
• Neurons/drug effects
• Neurons/metabolism
• Neurons/pathology
• Lipid Peroxidation/drug effects
• Glycogen Synthase Kinase 3 beta/metabolism
• Tretinoin/pharmacology

• AppNL-G-F
• amyloid-β
• imaging mass cytometry
• neuropathology
• oligomers

• Edmond J. Safra Foundation and Lily Safra and a National Institute for Health Research
• UK Dementia Research Institute
• UK Medical Research Council
• Alzheimer's Society
• NIHR Biomedical Research Centre

• National Natural Science Foundation of China

• Alzheimer's disease
• Aβ aggregates
• Calcium signal
• Endoplasmic reticulum-mitochondrial-Ca(2+)
• Hyperoside
• Mitochondrial membrane potential
• Neurotoxicity
• Ryanodine receptors

• Indole alkaloids
• Molecular dynamic simulation
• Neurodegenerative diseases
• β-Sheet

Irisin, the circulating peptide originating from fibronectin type III domain-containing protein 5 (FNDC5), is mainly expressed by muscle fibers under peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) control during exercise. In addition to several beneficial effects on health, physical activity positively affects nervous system functioning, particularly the hippocampus, resulting in amelioration of cognition impairments. Recently, FNDC5/irisin detection in hippocampal neurons and the presence of irisin in the cerebrospinal fluid opened a new intriguing chapter in irisin history. Interestingly, in the hippocampus of mice, exercise increases FNDC5 levels and upregulates brain-derived neurotrophic factor (BDNF) expression. BDNF, displaying neuroprotection and anti-inflammatory effects, is mainly produced by microglia and astrocytes. In this review, we discuss how these glial cells can morphologically and functionally switch during neuroinflammation by modulating the expression of a plethora of neuroprotective or neurotoxic factors. We also focus on studies investigating the irisin role in neurodegenerative diseases (ND). The emerging involvement of irisin as a mediator of the multiple positive effects of exercise on the brain needs further studies to better deepen this issue and the potential use in therapeutic approaches for neuroinflammation and ND.

• FNDC5
• irisin
• neurodegeneration
• neuroinflammation

• Animals
• Brain-Derived Neurotrophic Factor/metabolism
• Exercise/physiology
• Fibronectins/genetics
• Fibronectins/metabolism
• Hippocampus/metabolism
• Humans
• Inflammation/etiology
• Inflammation/metabolism
• Mice
• Models, Neurological
• Neurodegenerative Diseases/etiology
• Neurodegenerative Diseases/metabolism
• Neuroimmunomodulation
• Physical Conditioning, Animal/physiology

Mesenchymal stem cells (MSCs) have been explored as promising tools for treatment of several neurological and neurodegenerative diseases. MSCs release abundant extracellular vesicles (EVs) containing a variety of biomolecules, including mRNAs, miRNAs, and proteins. We hypothesized that EVs derived from human Wharton’s jelly would act as mediators of the communication between hMSCs and neurons and could protect hippocampal neurons from damage induced by Alzheimer’s disease-linked amyloid beta oligomers (AβOs).

We isolated and characterized EVs released by human Wharton’s jelly mesenchymal stem cells (hMSC-EVs). The neuroprotective action of hMSC-EVs was investigated in primary hippocampal cultures exposed to AβOs.

hMSC-EVs were internalized by hippocampal cells in culture, and this was enhanced in the presence of AβOs in the medium. hMSC-EVs protected hippocampal neurons from oxidative stress and synapse damage induced by AβOs. Neuroprotection by hMSC-EVs was mediated by catalase and was abolished in the presence of the catalase inhibitor, aminotriazole.

hMSC-EVs protected hippocampal neurons from damage induced by AβOs, and this was related to the transfer of enzymatically active catalase contained in EVs. Results suggest that hMSC-EVs should be further explored as a cell-free therapeutic approach to prevent neuronal damage in Alzheimer’s disease.

• Alzheimer's disease
• BACE-1 inhibitors
• Fyn
• GSK-3β
• amyloid hypothesis
• amyloid-β
• β-secretase

In the sanctity of pure drug discovery, objective reasoning can become clouded when pursuing ideas that appear unorthodox, but are spot on physiologically. To put this into historical perspective, it was an unorthodox idea in the 1950’s to suggest that warfarin, a rat poison, could be repositioned into a breakthrough drug in humans to protect against strokes as a blood thinner. Yet it was approved in 1954 as Coumadin^® and has been prescribed to billions of patients as a standard of care. Similarly, no one can forget the horrific effects of thalidomide, prescribed or available without a prescription, as both a sleeping pill and “morning sickness” anti-nausea medication targeting pregnant women in the 1950’s. The “thalidomide babies” became the case-in-point for the need of strict guidelines by the U.S. Food & Drug Administration (FDA) or full multi-species teratogenicity testing before drug approval. More recently it was found that thalidomide is useful in graft versus host disease, leprosy and resistant tuberculosis treatment, and as an anti-angiogenesis agent as a breakthrough drug for multiple myeloma (except for pregnant female patients). Decades of diabetes drug discovery research has historically focused on every possible angle, except, the energy-out side of the equation, namely, raising mitochondrial energy expenditure with chemical uncouplers. The idea of “social responsibility” allowed energy-in agents to be explored and the portfolio is robust with medicines of insulin sensitizers, insulin analogues, secretagogues, SGLT2 inhibitors, etc., but not energy-out medicines. The primary reason? It appeared unorthodox, to return to exploring a drug platform used in the 1930s in over 100,000 obese patients used for weight loss. This is over 80-years ago and prior to Dr Peter Mitchell explaining the mechanism of how mitochondrial uncouplers, like 2,4-dinitrophenol (DNP) even worked by three decades later in 1961. Although there is a clear application for metabolic disease, it was not until recently that this platform was explored for its merit at very low, weight-neutral doses, for treating insidious human illnesses and completely unrelated to weight reduction. It is known that mitochondrial uncouplers specifically target the entire organelle’s physiology non-genomically. It has been known for years that many neuromuscular and neurodegenerative diseases are associated with overt production of reactive oxygen species (ROSs), a rise in isoprostanes (biomarker of mitochondrial ROSs in urine or blood) and poor calcium (Ca²⁺) handing. It has also been known that mitochondrial uncouplers lower ROS production and Ca²⁺ overload. There is evidence that elevation of isoprostanes precedes disease onset, in Alzheimer’s Disease (AD). It is also curious, why so many neurodegenerative diseases of known and unknown etiology start at mid-life or later, such as Multiple Sclerosis (MS), Huntington Disease (HD), AD, Parkinson Disease, and Amyotrophic Lateral Sclerosis (ALS). Is there a relationship to a buildup of mutations that are sequestered over time due to ROSs exceeding the rate of repair? If ROS production were managed, could disease onset due to aging be delayed or prevented? Is it possible that most, if not all neurodegenerative diseases are manifested through mitochondrial dysfunction? Although DNP, a historic mitochondrial uncoupler, was used in the 1930s at high doses for obesity in well over 100,000 humans, and so far, it has never been an FDA-approved drug. This review will focus on the application of using DNP, but now, repositioned as a potential disease-modifying drug for a legion of insidious diseases at much lower and paradoxically, weight neutral doses. DNP will be addressed as a treatment for “metabesity”, an emerging term related to the global comorbidities associated with the over-nutritional phenotype; obesity, diabetes, nonalcoholic steatohepatitis (NASH), metabolic syndrome, cardiovascular disease, but including neurodegenerative disorders and accelerated aging. Some unexpected drug findings will be discussed, such as DNP’s induction of neurotrophic growth factors involved in neuronal heath, learning and cognition. For the first time in 80’s years, the FDA has granted (to Mitochon Pharmaceutical, Inc., Blue Bell, PA, USA) an open Investigational New Drug (IND) approval to begin rigorous clinical testing of DNP for safety and tolerability, including for the first ever, pharmacokinetic profiling in humans. Successful completion of Phase I clinical trial will open the door to explore the merits of DNP as a possible treatment of people with many truly unmet medical needs, including those suffering from HD, MS, PD, AD, ALS, Duchenne Muscular Dystrophy (DMD), and Traumatic Brain Injury (TBI).

• 2,4-dinitrophenol (DNP)
• Brain-derived neurotrophic factor (BDNF)
• Duchenne Muscular Dystrophy
• Huntington’s Disease
• Multiple Sclerosis
• Traumatic Brain Injury
• anti-aging
• metabesity
• mitochondrial uncoupler
• neurodegeneration

• 2,4-Dinitrophenol/metabolism
• Adenosine Triphosphate/metabolism
• Animals
• Calcium/metabolism
• Cognition
• Humans
• Medicine
• Reactive Oxygen Species/metabolism

• Amyloid β
• Atrophy
• Gastric mucosa
• Gastrokine 1
• NKX6.3

• Amyloid beta-Peptides/genetics
• Amyloid beta-Peptides/metabolism
• Antigens, Bacterial/analysis
• Bacterial Proteins/analysis
• Carcinogenesis/pathology
• Cell Line
• Down-Regulation
• Epithelial Cells
• Gastrectomy
• Gastric Mucosa/cytology
• Gastric Mucosa/pathology
• Gastric Mucosa/surgery
• Gastritis, Atrophic/microbiology
• Gastritis, Atrophic/pathology
• Helicobacter Infections/microbiology
• Helicobacter Infections/pathology
• Helicobacter pylori/isolation & purification
• Homeodomain Proteins/genetics
• Homeodomain Proteins/metabolism
• Humans
• Precancerous Conditions/microbiology
• Precancerous Conditions/pathology
• RNA, Small Interfering/metabolism
• Stomach Neoplasms/microbiology
• Stomach Neoplasms/pathology
• Stomach Neoplasms/surgery
• Transcription Factors/genetics
• Transcription Factors/metabolism

• Alzheimer’s disease
• amyloid
• drug discovery
• therapeutics
• toxicity

• Alzheimer Disease/drug therapy
• Alzheimer Disease/metabolism
• Amyloid beta-Peptides/antagonists & inhibitors
• Amyloid beta-Peptides/metabolism
• Animals
• Antibodies, Monoclonal, Humanized/administration & dosage
• Brain/drug effects
• Brain/metabolism
• Drug Delivery Systems/trends
• Drug Discovery/trends
• Humans
• tau Proteins/antagonists & inhibitors
• tau Proteins/metabolism

• 3xTg-AD
• Aggregation
• Alzheimer's disease
• Amyloid β
• Neuroprotection
• SH-SY5Y

• Alzheimer's disease
• amyloid-β
• catalase
• cytokine action
• endocytosis
• extracellular vesicles
• hippocampus
• mesenchymal stem cells (MSCs)
• oligomers
• oxidative stress
• synapse

• Alzheimer Disease/drug therapy
• Alzheimer Disease/metabolism
• Amyloid beta-Peptides/antagonists & inhibitors
• Amyloid beta-Peptides/chemistry
• Amyloid beta-Peptides/metabolism
• Animals
• Antibodies/chemistry
• Antibodies/metabolism
• Humans
• Protein Conformation
• Small Molecule Libraries/chemistry
• Small Molecule Libraries/pharmacology
• Vaccines/chemistry
• Vaccines/pharmacology

• Amyloid aggregation
• Fibril
• Neurodegenerative diseases
• Oligomer
• Structure
• Therapeutic approaches

• Amyloid/drug effects
• Amyloid/metabolism
• Animals
• Biophysical Phenomena
• Humans
• Neurodegenerative Diseases/metabolism
• Neurodegenerative Diseases/therapy
• Protein Aggregation, Pathological/metabolism
• Protein Aggregation, Pathological/therapy
• Protein Folding

• Abeta
• Alzheimer's disease
• High fat diet
• Memory
• Thymol

• Amyloid beta-Peptides/administration & dosage
• Amyloid beta-Peptides/toxicity
• Animals
• Anti-Infective Agents/administration & dosage
• Avoidance Learning/drug effects
• Avoidance Learning/physiology
• Diet, High-Fat/adverse effects
• Hippocampus/drug effects
• Hippocampus/pathology
• Injections, Intraventricular
• Male
• Memory Disorders/chemically induced
• Memory Disorders/drug therapy
• Memory Disorders/pathology
• Peptide Fragments/administration & dosage
• Peptide Fragments/toxicity
• Random Allocation
• Rats
• Rats, Wistar
• Thymol/administration & dosage
• Treatment Outcome

• AMP-activated kinase (AMPK)
• ATP
• Alzheimer disease
• GLUTs
• N-methyl-d-aspartate receptor (NMDA receptor, NMDAR)
• amyloid-β oligomers
• energy metabolism

• 3xTg-AD
• Alzheimer’s disease
• Amyloid β
• SH-SY5Y
• SLM
• aggregation
• neuroprotection

• Aggregate inhibitor
• Biomarker
• Heteromer
• Neurodegenerative diseases
• Oligomer

The azo dye carmoisine has a significant inhibitory effect on fibrillogenesis in lysozyme.

Brain insulin signaling deficits contribute to multiple pathological features of Alzheimer's disease (AD). Although intranasal insulin has shown efficacy in patients with AD, the underlying mechanisms remain largely unillustrated. Here, we demonstrate that intranasal insulin improves cognitive deficits, ameliorates defective brain insulin signaling, and strongly reduces β‐amyloid (Aβ) production and plaque formation after 6 weeks of treatment in 4.5‐month‐old APPswe/PS1dE9 (APP/PS1) mice. Furthermore, c‐Jun N‐terminal kinase activation, which plays a pivotal role in insulin resistance and AD pathologies, is significantly inhibited. The alleviation of amyloid pathology by intranasal insulin results mainly from enhanced nonamyloidogenic processing and compromised amyloidogenic processing of amyloid precursor protein (APP), and from a reduction in apolipoprotein E protein which is involved in Aβ metabolism. In addition, intranasal insulin effectively promotes hippocampal neurogenesis in APP/PS1 mice. This study, exploring the mechanisms underlying the beneficial effects of intranasal insulin on Aβ pathologies in vivo for the first time, highlights important preclinical evidence that intranasal insulin is potentially an effective therapeutic method for the prevention and treatment of AD.

• APP processing
• APP/PS1
• Alzheimer's disease
• amyloid pathology
• insulin signaling

Alpha-synuclein (α-Syn) aggregation into oligomers and fibrils is associated with dopaminergic neuron loss occurring in Parkinson’s disease (PD) pathogenesis. Compounds that modulate α-Syn aggregation and interact with preformed fibrils/oligomers and convert them to less toxic species could have promising applications in the drug development efforts against PD. Curcumin is one of the Asian food ingredient which showed promising role as therapeutic agent against many neurological disorders including PD. However, the instability and low solubility makes it less attractive for the drug development. In this work, we selected various curcumin analogs and studied their toxicity, stability and efficacy to interact with different α-Syn species and modulation of their toxicity. We found a subset of curcumin analogs with higher stability and showed that curcumin and its various analogs interact with preformed fibrils and oligomers and accelerate α-Syn aggregation to produce morphologically different amyloid fibrils in vitro. Furthermore, these curcumin analogs showed differential binding with the preformed α-Syn aggregates. The present data suggest the potential role of curcumin analogs in modulating α-Syn aggregation.

• Amyloid-β
• Immunotherapy
• Inflammation
• Oligomers
• Size
• Toxicity

• Alzheimer Disease/immunology
• Alzheimer Disease/therapy
• Amyloid beta-Peptides/chemistry
• Amyloid beta-Peptides/immunology
• Amyloid beta-Peptides/toxicity
• Clinical Trials as Topic
• Humans
• Immunotherapy/methods
• Peptide Fragments/chemistry
• Protein Multimerization

• R01 AG054025 NIA NIH HHS

• Amyloid
• Aβ
• ESI-IMS–MS
• Ligand screening
• Small molecule inhibitor

• Amyloid beta-Peptides/antagonists & inhibitors
• Amyloid beta-Peptides/chemistry
• High-Throughput Screening Assays
• Humans
• Hydrogen-Ion Concentration
• Ligands
• Models, Molecular
• Peptide Fragments/antagonists & inhibitors
• Peptide Fragments/chemistry
• Protein Aggregates/drug effects
• Protein Binding
• Protein Conformation
• Small Molecule Libraries/chemistry
• Solutions
• Spectrometry, Mass, Electrospray Ionization/methods

• BB/H014713/1 Biotechnology and Biological Sciences Research Council
• 322408 European Research Council
• BB/I015361/1 Biotechnology and Biological Sciences Research Council
• BB/F01614X/1 Biotechnology and Biological Sciences Research Council
• BB/E012558/1 Biotechnology and Biological Sciences Research Council

Amyloid fibril formation of hen lysozyme (HEWL) can be attenuated by fast green FCF.

• Anti-amyloidogenic
• Fibrillation products cytotoxicity
• Polyphenol

• Amyloid/chemistry
• Animals
• Antioxidants/chemistry
• Antioxidants/pharmacology
• Cell Shape/drug effects
• Cell Survival
• Cinnamates/chemistry
• Cinnamates/pharmacology
• Depsides/chemistry
• Depsides/pharmacology
• Drug Evaluation, Preclinical
• Hydrophobic and Hydrophilic Interactions
• Inhibitory Concentration 50
• Muramidase/chemistry
• PC12 Cells
• Protein Aggregation, Pathological/prevention & control
• Protein Stability
• Protein Structure, Secondary
• Rats
• Resveratrol
• Stilbenes/chemistry
• Stilbenes/pharmacology
• Rosmarinic Acid

Fluorinated alcohols such as hexafluoroisopropanol (HFIP) and trifluoroethanol (TFE) have the ability to promote α-helix and β-hairpin structure in proteins and peptides. HFIP has been used extensively to dissolve various amyloidogenic proteins and peptides including Aβ, in order to ensure their monomeric status. In this paper, we have investigated the self-assembly of Aβ40, Aβ42, and Aβ43 in aqueous mixtures of fluorinated alcohols from freshly dissolved stock solutions in HFIP. We have observed that formation of fibrillar and non-fibrillar structures are dependent on the solvent composition. Peptides form fibrils with ease when reconstituted in deionized water from freshly dissolved HFIP stocks. In aqueous mixtures of fluorinated alcohols, either predominant fibrillar structures or clustered aggregates were observed. Aqueous mixtures of 20% HFIP are more favourable for Aβ fibril formation as compared to 20% TFE. When Aβ40, Aβ42, and Aβ43 stocks in HFIP are diluted in 50% aqueous mixtures in phosphate buffer or deionized water followed by slow evaporation of HFIP, Aβ peptides form fibrils in phosphate buffer and deionized water. The clustered structures could be off-pathway aggregates. Aβ40, Aβ42, and Aβ43 showed significant α-helical content in freshly dissolved HFIP stocks. The α-helical conformational intermediate in Aβ40, Aβ42, and Aβ43 could favour the formation of both fibrillar and non-fibrillar aggregates depending on solvent conditions and rate of α-helical to β-sheet transition.

• Amyloid beta-Peptides/chemistry
• Circular Dichroism
• Halogenation
• Humans
• Microscopy, Electron, Transmission
• Peptide Fragments/chemistry
• Propanols/chemistry
• Protein Conformation
• Solvents
• Spectrometry, Fluorescence
• Spectroscopy, Fourier Transform Infrared
• Trifluoroethanol/chemistry

Alzheimer’s disease (AD) is the most common form of dementia in the elderly, and affects millions of people worldwide. As the number of AD cases continues to increase in both developed and developing countries, finding therapies that effectively halt or reverse disease progression constitutes a major research and public health challenge. Since the identification of the amyloid-β peptide (Aβ) as the major component of the amyloid plaques that are characteristically found in AD brains, a major effort has aimed to determine whether and how Aβ leads to memory loss and cognitive impairment. A large body of evidence accumulated in the past 15 years supports a pivotal role of soluble Aβ oligomers (AβOs) in synapse failure and neuronal dysfunction in AD. Nonetheless, a number of basic questions, including the exact molecular composition of the synaptotoxic oligomers, the identity of the receptor(s) to which they bind, and the signaling pathways that ultimately lead to synapse failure, remain to be definitively answered. Here, we discuss recent advances that have illuminated our understanding of the chemical nature of the toxic species and the deleterious impact they have on synapses, and have culminated in the proposal of an Aβ oligomer hypothesis for Alzheimer’s pathogenesis. We also highlight outstanding questions and challenges in AD research that should be addressed to allow translation of research findings into effective AD therapies.

• Alzheimer’s disease
• amyloid-β oligomers
• memory loss
• neuronal dysfunction
• synapse failure

A family of 21 polyphenolic compounds consisting of those found naturally in danshen and their analogues were synthesized and subsequently screened for their anti-amyloidogenic activity against the amyloid beta peptide (Aβ₄₂) of Alzheimer’s disease. After 24 h incubation with Aβ₄₂, five compounds reduced thioflavin T (ThT) fluorescence, indicative of their anti-amyloidogenic propensity (p < 0.001). TEM and immunoblotting analysis also showed that selected compounds were capable of hindering fibril formation even after prolonged incubations. These compounds were also capable of rescuing the yeast cells from toxic changes induced by the chemically synthesized Aβ₄₂. In a second assay, a Saccharomyces cerevisiae AHP1 deletant strain transformed with GFP fused to Aβ₄₂ was treated with these compounds and analyzed by flow cytometry. There was a significant reduction in the green fluorescence intensity associated with 14 compounds. We interpret this result to mean that the compounds had an anti-amyloid-aggregation propensity in the yeast and GFP-Aβ₄₂ was removed by proteolysis. The position and not the number of hydroxyl groups on the aromatic ring was found to be the most important determinant for the anti-amyloidogenic properties.

• Amyloid/drug effects
• Amyloid beta-Peptides/toxicity
• Peptide Fragments/toxicity
• Peroxiredoxins/genetics
• Plant Extracts/chemistry
• Plant Extracts/pharmacology
• Polyphenols/chemistry
• Polyphenols/pharmacology
• Saccharomyces cerevisiae/drug effects
• Saccharomyces cerevisiae/metabolism
• Salvia miltiorrhiza/chemistry
• Small Molecule Libraries/chemistry
• Small Molecule Libraries/pharmacology

Conversion of amyloid fibrils by many peptides/proteins involves cytotoxic helix-rich oligomers. However, their toxicity and biophysical studies remain largely unknown due to their highly dynamic nature. To address this, we chose two helical peptides (melittin, Mel and pancreatic polypeptide, PP) and studied their aggregation and toxicity. Mel converted its random coil structure to oligomeric helical structure upon binding to heparin; however, PP remained as helix after oligomerization. Interestingly, similar to Parkinson’s associated α-synuclein (AS) oligomers, Mel and PP also showed tinctorial properties, higher hydrophobic surface exposure, cellular toxicity and membrane pore formation after oligomerization in the presence of heparin. We suggest that helix-rich oligomers with exposed hydrophobic surface are highly cytotoxic to cells irrespective of their disease association. Moreover as Mel and PP (in the presence of heparin) instantly self-assemble into stable helix-rich amyloidogenic oligomers; they could be represented as models for understanding the biophysical and cytotoxic properties of helix-rich intermediates in detail.

• Amyloid/chemistry
• Amyloid/metabolism
• Animals
• Bees
• Cell Line
• Heparin/metabolism
• Humans
• Melitten/chemistry
• Melitten/metabolism
• Models, Molecular
• Neurons/cytology
• Neurons/metabolism
• Neurotoxins/chemistry
• Neurotoxins/metabolism
• Pancreatic Polypeptide/chemistry
• Pancreatic Polypeptide/metabolism
• Protein Aggregates
• Protein Structure, Secondary

The search for therapeutic agents which bind specifically to precursor protein conformations and inhibit amyloid assembly is an important challenge. Identifying such inhibitors is difficult since many protein precursors of aggregation are partially folded or intrinsically disordered, ruling out structure-based design. Furthermore, inhibitors can act by a variety of mechanisms, including specific or non-specific binding, as well as colloidal inhibition. Here we report a high throughput method based on ion mobility spectrometry-mass spectrometry (IMS-MS) that is capable of rapidly detecting small molecules that bind to amyloid precursors, identifying the interacting protein species, and defining the mode of inhibition. Using this method we have classified a variety of small molecules that are potential inhibitors of human islet amyloid polypeptide (hIAPP) aggregation or amyloid-beta 1-40 (Aβ40) aggregation as either specific, non-specific, colloidal or non-interacting. We also demonstrate the ability of IMS-MS to screen for inhibitory small molecules in a 96-well plate format and use this to discover a new inhibitor of hIAPP amyloid assembly.