Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Bivalent ligand containing curcumin and cholesterol as fluorescence probe for Aβ plaques in Alzheimer's disease.

ABSTRACT: A recently developed bivalent ligand BMAOI 14 (7) has been evaluated for its capability to label and detect aggregated β-amyloid (Aβ) peptide as a fluorescent probe. This probe contains curcumin as the Aβ recognition moiety and cholesterol as an anchorage to the neuronal cell membrane/lipid rafts. The results demonstrate that 7 binds to the monomers, oligomers as well as fibrils of Aβ42 with low micromolar to submicromolar binding affinities. This chemical probe also has many of the required optical properties for use in imaging and can rapidly cross the blood-brain barrier (BBB) in vivo. Furthermore, 7 specifically binds to Aβ plaques in both AD human patients and APP transgenic mouse brain tissues. Collectively, these results suggest that 7 is a strong candidate as an Aβ-imaging agent and encourage further optimization of 7 as a new lead to develop the next generation of Aβ-imaging probes.

SUBMITTER: Liu K

PROVIDER: S-EPMC3367438 | biostudies-other | 2012 Feb

REPOSITORIES: biostudies-other

ACCESS DATA

Json Xml

Shared Molecules

Only show the datasets with similarity scores above: 0.5

Threshold

0.5

Similar Datasets

Aβ plaque-selective NIR fluorescence probe to differentiate Alzheimer's disease from tauopathies.

Project description:Selective detection and staining of toxic amyloid plaques, a potential biomarker present in the Alzheimer's disease (AD) brain is crucial for both clinical diagnosis and monitoring AD disease progression. Herein, we report a coumarin-quinoline (CQ) conjugate-based turn-on near-infrared (NIR) fluorescence probe for specific detection of β-amyloid (Aβ) aggregates. CQ probe is highly sensitive and exhibits ~100-fold fluorescence enhancement in vitro upon binding Aβ aggregates with enhanced quantum yield. Furthermore, the probe has ~10-fold higher binding affinity towards Aβ aggregates (86nM) compared to commonly used Thioflavin T. Most importantly, CQ probe displays unambiguous selectivity towards Aβ aggregates compared to other toxic protein aggregates such as tau, α-synuclein (α-Syn) and islet amyloid polypeptide (IAPP). In addition, CQ is nontoxic to neuronal cells and shows significant blood brain barrier permeability. Remarkably, CQ stains Aβ plaques in human brain tissue over co-existing tau aggregates and neurofibrillary tangles (NFTs), which are associated in AD and tauopathies. This is a highly desirable attribute to distinguish AD from tau pathology and mixed dementia.

| S-EPMC6370041 | biostudies-literature

Curcumin Targeted, Polymalic Acid-Based MRI Contrast Agent for the Detection of Aβ Plaques in Alzheimer's Disease.

Project description:Currently, there is no gadolinium-based contrast agent available for conventional magnetic resonance imaging (MRI) detection of amyloidal beta (Aβ) plaques in Alzheimer's disease (AD). Its timely finding would be vital for patient survival and quality of life. Curcumin (CUR), a common Indian spice effectively binds to Aβ plaques which is a hallmark of AD. To address this binding, we have designed a novel nanoimaging agent (NIA) based on nature-derived poly(β-l-malic acid) (PMLA) containing covalently attached gadolinium-DOTA(Gd-DOTA) and nature-derived CUR. The all-in-one agent recognizes and selectively binds to Aβ plaques and is detected by MRI. It efficiently detected Aβ plaques in human and mouse samples by an ex vivo staining. The method can be useful in clinic for safe and noninvasive diagnosis of AD.

| S-EPMC4794283 | biostudies-literature

Unsaturated Fatty Acids Are Decreased in Aβ Plaques in Alzheimer's Disease.

Project description:Alzheimer's disease (AD) is characterized by the accumulation of amyloid-beta (Aβ) plaques in the brain, contributing to neurodegeneration. This study investigates lipid alterations within these plaques using a novel, label-free, multimodal approach. Combining infrared (IR) imaging, machine learning, laser microdissection (LMD), and flow injection analysis mass spectrometry (FIA-MS), we provide the first comprehensive lipidomic analysis of chemically unaltered Aβ plaques in post-mortem human AD brain tissue. IR imaging revealed decreased lipid unsaturation within plaques, evidenced by a reduction in the alkene (=C-H) stretching vibration band. The high spatial resolution of IR imaging, coupled with machine learning-based plaque detection, enabled precise and label-free extraction of plaques via LMD. Subsequent FIA-MS analysis confirmed a significant increase in short-chain saturated lipids and a concomitant decrease in long-chain unsaturated lipids within plaques compared to the surrounding tissue. These findings highlight a substantial depletion of unsaturated fatty acids (UFAs) in Aβ plaques, suggesting a pivotal role for lipid dysregulation and oxidative stress in AD pathology. This study advances our understanding of the molecular landscape of Aβ plaques and underscores the potential of lipid-based therapeutic strategies in AD.

| S-EPMC11742699 | biostudies-literature

Bivalent ligands incorporating curcumin and diosgenin as multifunctional compounds against Alzheimer's disease.

Project description:In an effort to combat the multifaceted nature of Alzheimer's disease (AD) progression, a series of multifunctional, bivalent compounds containing curcumin and diosgenin were designed, synthesized, and biologically characterized. Screening results in MC65 neuroblastoma cells established that compound 38 with a spacer length of 17 atoms exhibited the highest protective potency with an EC50 of 111.7 ± 9.0 nM. A reduction in protective activity was observed as spacer length was increased up to 28 atoms and there is a clear structural preference for attachment to the methylene carbon between the two carbonyl moieties of curcumin. Further study suggested that antioxidative ability and inhibitory effects on amyloid-β oligomer (AβO) formation may contribute to the neuroprotective outcomes. Additionally, compound 38 was found to bind directly to Aβ, similar to curcumin, but did not form complexes with the common biometals Cu, Fe, and Zn. Altogether, these results give strong evidence to support the bivalent design strategy in developing novel compounds with multifunctional ability for the treatment of AD.

| S-EPMC4641451 | biostudies-literature

Distinct transcriptomic responses to Aβ plaques, neurofibrillary tangles, and APOE in Alzheimer's disease.

Project description:IntroductionOmics studies have revealed that various brain cell types undergo profound molecular changes in Alzheimer's disease (AD) but the spatial relationships with plaques and tangles and APOE-linked differences remain unclear.MethodsWe performed laser capture microdissection of amyloid beta (Aβ) plaques, the 50 μm halo around them, tangles with the 50 μm halo around them, and areas distant (> 50 μm) from plaques and tangles in the temporal cortex of AD and control donors, followed by RNA-sequencing.ResultsAβ plaques exhibited upregulated microglial (neuroinflammation/phagocytosis) and downregulated neuronal (neurotransmission/energy metabolism) genes, whereas tangles had mostly downregulated neuronal genes. Aβ plaques had more differentially expressed genes than tangles. We identified a gradient Aβ plaque > peri-plaque > tangle > distant for these changes. AD APOE ε4 homozygotes had greater changes than APOE ε3 across locations, especially within Aβ plaques.DiscussionTranscriptomic changes in AD consist primarily of neuroinflammation and neuronal dysfunction, are spatially associated mainly with Aβ plaques, and are exacerbated by the APOE ε4 allele.

| S-EPMC10792109 | biostudies-literature

Differentiating Aβ40 and Aβ42 in amyloid plaques with a small molecule fluorescence probe.

Project description:Differentiating amyloid beta (Aβ) subspecies Aβ40 and Aβ42 has long been considered an impossible mission with small-molecule probes. In this report, based on recently published structures of Aβ fibrils, we designed iminocoumarin-thiazole (ICT) fluorescence probes to differentiate Aβ40 and Aβ42, among which Aβ42 has much higher neurotoxicity. We demonstrated that ICTAD-1 robustly responds to Aβ fibrils, evidenced by turn-on fluorescence intensity and red-shifting of emission peaks. Remarkably, ICTAD-1 showed different spectra towards Aβ40 and Aβ42 fibrils. In vitro results demonstrated that ICTAD-1 could be used to differentiate Aβ40/42 in solutions. Moreover, our data revealed that ICTAD-1 could be used to separate Aβ40/42 components in plaques of AD mouse brain slides. In addition, two-photon imaging suggested that ICTAD-1 was able to cross the BBB and label plaques in vivo. Interestingly, we observed that ICTAD-1 was specific toward plaques, but not cerebral amyloid angiopathy (CAA) on brain blood vessels. Given Aβ40 and Aβ42 species have significant differences of neurotoxicity, we believe that ICTAD-1 can be used as an important tool for basic studies and has the potential to provide a better diagnosis in the future.

| S-EPMC8159352 | biostudies-literature

Accelerated microglial pathology is associated with Aβ plaques in mouse models of Alzheimer's disease.

Project description:Microglia integrate within the neural tissue with a distinct ramified morphology through which they scan the surrounding neuronal network. Here, we used a digital tool for the quantitative morphometric characterization of fine cortical microglial structures in mice, and the changes they undergo with aging and in Alzheimer's-like disease. We show that, compared with microglia in young mice, microglia in old mice are less ramified and possess fewer branches and fine processes along with a slightly increased proinflammatory cytokine expression. A similar microglial pathology appeared 6-12 months earlier in mouse models of Alzheimer's disease (AD), along with a significant increase in brain parenchyma lacking coverage by microglial processes. We further demonstrate that microglia near amyloid plaques acquire unique activated phenotypes with impaired process complexity. We thus show that along with a chronic proinflammatory reaction in the brain, aging causes a significant reduction in the capacity of microglia to scan their environment. This type of pathology is markedly accelerated in mouse models of AD, resulting in a severe microglial process deficiency, and possibly contributing to enhanced cognitive decline.

| S-EPMC4326940 | biostudies-literature

Distinct Transcriptomic Responses to Aβ plaques, Neurofibrillary Tangles, and <i>APOE</i> in Alzheimer's Disease.

Project description:IntroductionOmics studies have revealed that various brain cell types undergo profound molecular changes in Alzheimer's disease (AD) but the spatial relationships with plaques and tangles and APOE -linked differences remain unclear.MethodsWe performed laser capture microdissection of Aβ plaques, the 50μm halo around them, tangles with the 50μm halo around them, and areas distant (>50μm) from plaques and tangles in the temporal cortex of AD and control donors, followed by RNA-sequencing.ResultsAβ plaques exhibited upregulated microglial (neuroinflammation/phagocytosis) and downregulated neuronal (neurotransmission/energy metabolism) genes, whereas tangles had mostly downregulated neuronal genes. Aβ plaques had more differentially expressed genes than tangles. We identified a gradient Aβ plaque>peri-plaque>tangle>distant for these changes. AD APOE ε4 homozygotes had greater changes than APOE ε3 across locations, especially within Aβ plaques.DiscussionTranscriptomic changes in AD consist primarily of neuroinflammation and neuronal dysfunction, are spatially associated mainly with Aβ plaques, and are exacerbated by the APOE ε4 allele.

| S-EPMC10055287 | biostudies-literature

Unspecific binding of cRNA probe to plaques in two mouse models for Alzheimer's disease.

Project description:BackgroundAlzheimer's disease (AD) is characterized by the pathological deposition of amyloid-β (Aβ) protein-containing plaques. Microglia and astrocytes are commonly attracted to the plaques by an unknown mechanism that may involve cell adhesion. One cell adhesion family of proteins, the cadherins, are widely expressed in the central nervous system. Therefore, our study was designed to map the expression of cadherins in AD mouse brains. A particular focus was on plaques because diverse mRNA-species were found in plaques and their surrounding area in brains of AD patients.MethodsIn this study, we used in situ hybridization to visualize cadherin expression in brains of two mouse models for AD (APP/PS1 and APP23).ResultsA variable number of plaques was detected in transgenic brain sections, depending on the probe used. Our first impression was that the cadherin probes visualized specific mRNA expression in plaques and that endogenous staining was unaffected. However, control experiments revealed unspecific binding with sense probes. Further experiments with variations in probe length, probe sequence, molecular tag and experimental procedure lead us to conclude that cRNA probes bind generally and in an unspecific manner to plaques.ConclusionsWe demonstrate unspecific binding of cRNA probes to plaques in two mouse models for AD. The widespread and general staining of the plaques prevented us from studying endogenous expression of cadherins in transgenic brain by in situ hybridization.

| S-EPMC5159973 | biostudies-literature

A comparison of the location in membranes of curcumin and curcumin-derived bivalent compounds with potential neuroprotective capacity for Alzheimer's disease.

Project description:Curcumin and two bivalent compounds, namely 17MD and 21MO, both obtained by conjugation of curcumin with a steroid molecule that acts as a membrane anchor, were comparatively studied. When incorporated into 1,2-dipalmitoyl-sn-glycero-3-phosphocholine the compounds showed a very limited solubility in the model membranes. Curcumin and the two bivalent compounds were also incorporated in membranes of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine and quenching the fluorescence of pure curcumin or of the curcumin moiety in the bivalent compounds by acrylamide it was seen that curcumin was accessible to this water soluble quencher but the molecule was somehow located in a hydrophobic environment. This was confirmed by quenching with doxyl-phosphatidylcholines, indicating that the curcumin moieties of 17MD and 21MO were in a more polar environment than pure curcumin itself. 1H NOESY MAS-NMR analysis supports this notion by showing that the orientation of curcumin was parallel to the plane of the membrane surface close to C2 and C3 of the fatty acyl chains, while the curcumin moiety of 17MD and 21MO positioned close to the polar part of the membrane with the steroid moiety in the centre of the membrane. Molecular dynamics studies were in close agreement with the experimental results with respect to the likely proximity of the protons studied by NMR and show that 17MD and 21MO have a clear tendency to aggregate in a fluid membrane. The anchorage of the bivalent compounds to the membrane leaving the curcumin moiety near the polar part may be very important to facilitate the bioactivity of the curcumin moiety when used as anti-Alzheimer drugs.

| S-EPMC7965246 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data