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1.
Chem Sci ; 13(27): 8104-8116, 2022 Jul 13.
Article in English | MEDLINE | ID: mdl-35919434

ABSTRACT

Small molecules and antibodies are normally considered separately in drug discovery, except in the case of covalent conjugates. We unexpectedly discovered several small molecules that could inhibit or enhance antibody-epitope interactions which opens new possibilities in drug discovery and therapeutic modulation of auto-antibodies. We first discovered a small molecule, CRANAD-17, that enhanced the binding of an antibody to amyloid beta (Aß), one of the major hallmarks of Alzheimer's disease, by stable triplex formation. Next, we found several small molecules that altered antibody-epitope interactions of tau and PD-L1 proteins, demonstrating the generality of this phenomenon. We report a new screening technology for ligand discovery, screening platform based on epitope alteration for drug discovery (SPEED), which is label-free for both the antibody and small molecule. SPEED, applied to an Aß antibody, led to the discovery of a small molecule, GNF5837, that inhibits Aß aggregation and another, obatoclax, that binds Aß plaques and can serve as a fluorescent reporter in brain slices of AD mice. We also found a small molecule that altered the binding between Aß and auto-antibodies from AD patient serum. SPEED reveals the sensitivity of antibody-epitope interactions to perturbation by small molecules and will have multiple applications in biotechnology and drug discovery.

2.
Sci Rep ; 8(1): 1144, 2018 01 18.
Article in English | MEDLINE | ID: mdl-29348604

ABSTRACT

Amyloid-beta protein (Aß) deposition is a pathological hallmark of Alzheimer's disease (AD). Aß deposition triggers both pro-neuroinflammatory microglial activation and neurofibrillary tangle formation. Cromolyn sodium is an asthma therapeutic agent previously shown to reduce Aß levels in transgenic AD mouse brains after one-week of treatment. Here, we further explored these effects as well as the mechanism of action of cromolyn, alone, and in combination with ibuprofen in APPSwedish-expressing Tg2576 mice. Mice were treated for 3 months starting at 5 months of age, when the earliest stages of ß-amyloid deposition begin. Cromolyn, alone, or in combination with ibuprofen, almost completely abolished longer insoluble Aß species, i.e. Aß40 and Aß42, but increased insoluble Aß38 levels. In addition to its anti-aggregation effects on Aß, cromolyn, alone, or plus ibuprofen, but not ibuprofen alone, increased microglial recruitment to, and phagocytosis of ß-amyloid deposits in AD mice. Cromolyn also promoted Aß42 uptake in microglial cell-based assays. Collectively, our data reveal robust effects of cromolyn, alone, or in combination with ibuprofen, in reducing aggregation-prone Aß levels and inducing a neuroprotective microglial activation state favoring Aß phagocytosis versus a pro-neuroinflammatory state. These findings support the use of cromolyn, alone, or with ibuprofen, as a potential AD therapeutic.


Subject(s)
Alzheimer Disease/drug therapy , Amyloid beta-Protein Precursor/antagonists & inhibitors , Cromolyn Sodium/pharmacology , Ibuprofen/pharmacology , Microglia/drug effects , Neuroprotective Agents/pharmacology , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/biosynthesis , Amyloid beta-Protein Precursor/genetics , Amyloid beta-Protein Precursor/metabolism , Animals , Anti-Asthmatic Agents/pharmacology , Brain/drug effects , Brain/metabolism , Brain/pathology , Disease Models, Animal , Drug Combinations , Drug Repositioning , Gene Expression , Humans , Male , Mice , Mice, Transgenic , Microglia/cytology , Microglia/metabolism , Neurons/drug effects , Neurons/metabolism , Neurons/pathology , Peptide Fragments/antagonists & inhibitors , Peptide Fragments/biosynthesis , Phagocytosis/drug effects , Transgenes
3.
Sci Rep ; 7(1): 10411, 2017 09 05.
Article in English | MEDLINE | ID: mdl-28874832

ABSTRACT

Recent evidence suggests the commensal microbiome regulates host immunity and influences brain function; findings that have ramifications for neurodegenerative diseases. In the context of Alzheimer's disease (AD), we previously reported that perturbations in microbial diversity induced by life-long combinatorial antibiotic (ABX) selection pressure in the APPSWE/PS1ΔE9 mouse model of amyloidosis is commensurate with reductions in amyloid-ß (Aß) plaque pathology and plaque-localised gliosis. Considering microbiota-host interactions, specifically during early post-natal development, are critical for immune- and neuro-development we now examine the impact of microbial community perturbations induced by acute ABX exposure exclusively during this period in APPSWE/PS1ΔE9 mice. We show that early post-natal (P) ABX treatment (P14-P21) results in long-term alterations of gut microbial genera (predominantly Lachnospiraceae and S24-7) and reduction in brain Aß deposition in aged APPSWE/PS1ΔE9 mice. These mice exhibit elevated levels of blood- and brain-resident Foxp3+ T-regulatory cells and display an alteration in the inflammatory milieu of the serum and cerebrospinal fluid. Finally, we confirm that plaque-localised microglia and astrocytes are reduced in ABX-exposed mice. These findings suggest that ABX-induced microbial diversity perturbations during post-natal stages of development coincide with altered host immunity mechanisms and amyloidosis in a murine model of AD.


Subject(s)
Alzheimer Disease/etiology , Amyloid beta-Protein Precursor/genetics , Amyloidosis/genetics , Anti-Bacterial Agents/pharmacology , Microbiota/drug effects , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Amyloid beta-Protein Precursor/metabolism , Amyloidosis/metabolism , Amyloidosis/pathology , Animals , Biodiversity , Biomarkers , Brain/metabolism , Brain/pathology , Disease Models, Animal , Gastrointestinal Microbiome , Inflammation Mediators/metabolism , Male , Metagenome , Metagenomics/methods , Mice , Mice, Transgenic , Neuroimmunomodulation/drug effects , Neuroimmunomodulation/genetics , Neuroimmunomodulation/immunology , Plaque, Amyloid/etiology , Plaque, Amyloid/metabolism , Plaque, Amyloid/pathology , RNA, Ribosomal, 16S/genetics
4.
EBioMedicine ; 24: 93-101, 2017 Oct.
Article in English | MEDLINE | ID: mdl-28919280

ABSTRACT

A central pathogenic event of Alzheimer's disease (AD) is the accumulation of the Aß42 peptide, which is generated from amyloid-ß precursor protein (APP) via cleavages by ß- and γ-secretase. We have developed a class of soluble 2-aminothiazole γ-secretase modulators (SGSMs) that preferentially decreases Aß42 levels. However, the effects of SGSMs in AD animals and cells expressing familial AD mutations, as well as the mechanism of γ-secretase modulation remain largely unknown. Here, a representative of this SGSM scaffold, SGSM-36, was investigated using animals and cells expressing FAD mutations. SGSM-36 preferentially reduced Aß42 levels without affecting either α- and ß-secretase processing of APP nor Notch processing. Furthermore, an allosteric site was identified within the γ-secretase complex that allowed access of SGSM-36 using cell-based, fluorescence lifetime imaging microscopy analysis. Collectively, these studies provide mechanistic insights regarding SGSMs of this class and reinforce their therapeutic potential in AD.


Subject(s)
Alzheimer Disease/drug therapy , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Amyloid beta-Peptides/metabolism , Enzyme Inhibitors/administration & dosage , Neurons/cytology , Presenilin-1/chemistry , Allosteric Site , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Amyloid Precursor Protein Secretases/chemistry , Animals , CHO Cells , Cells, Cultured , Cricetulus , Disease Models, Animal , Enzyme Inhibitors/pharmacology , Humans , Mice , Mice, Transgenic , Neurons/metabolism , Presenilin-1/metabolism , Protein Conformation/drug effects
5.
Sci Rep ; 7(1): 5722, 2017 07 18.
Article in English | MEDLINE | ID: mdl-28720893

ABSTRACT

Considerable evidence shows critical roles of intracellular pathogenic events of Alzheimer's disease (AD). In particular, intracellular amyloid-ß accumulation and oligomerization are early AD pathologic processes, which may lead to changes in inflammatory molecules and other AD-related pathological components. Curcumin and its analogs have been identified as potential drug candidates for AD. However, the effects of curcumin on intracellular AD pathologic processes remain largely unknown. Here we utilized a recently developed nanoplasmonic fiber tip probe (nFTP) technology and investigated whether curcumin leads to intracellular AD pathologic changes. We showed that our nFTP technology could robustly detect intracellular AD-related protein changes caused by a well-known inflammation inducer and a familial AD mutation. Intriguingly, curcumin remarkably reduced the level of intracellular oligomers while modestly reduced the level of an inflammatory cytokine. Thus, our results provided evidence that curcumin's mechanism of action in attenuating AD pathology is through a major role of decreasing oligomerization.


Subject(s)
Alzheimer Disease/drug therapy , Alzheimer Disease/pathology , Amyloid beta-Peptides/analysis , Curcumin/pharmacology , Cytoplasm/chemistry , Neuroprotective Agents/pharmacology , Peptide Fragments/analysis , Animals , Cells, Cultured , Cricetinae , Models, Biological , Nanotechnology , Surface Plasmon Resonance
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