A Copper-Selective Sensor and Its Inhibition of Copper-Amyloid Beta Aggregation

Copper is an essential trace metal for biological processes in humans and animals. A low level of copper detection at physiological pH using fluorescent probes is very important for in vitro applications, such as the detection of copper in water or urine, and in vivo applications, such as tracking t...

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Published in:	Biosensors (Basel) Vol. 14; no. 5; p. 247
Main Authors:	Nguyen, Ngoc Kim, Poduska, Bella, Franks, Mia, Bera, Manoranjan, MacCormack, Ian, Lin, Guoxing, Petroff, Alexander P, Das, Samir, Nag, Arundhati
Format:	Journal Article
Language:	English
Published:	Switzerland MDPI AG 14-05-2024
Subjects:	Affinity Aggregates Alzheimer Disease - drug therapy Alzheimer Disease - metabolism Alzheimer's disease Amyloid beta-Peptides - metabolism Amyloid beta-protein Biocompatibility Biological activity Biosensing Techniques Biosensors Chelating agents Chelating Agents - pharmacology Conjugates Copper Copper - chemistry Cu-amyloid beta Fluorescence fluorescent copper chelator Fluorescent Dyes Fluorescent indicators Homeostasis Humans In vivo methods and tests Ligands Low level Measurement Neurodegenerative diseases Neurological diseases non-amyloid aggregate inhibition Peptides Potash Potassium Protein Aggregates Selectivity Senile plaques Sensors Solvents Trace metals β-Amyloid United States Cu-amyloid beta fluorescent copper chelator non-amyloid aggregate inhibition
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Summary:	Copper is an essential trace metal for biological processes in humans and animals. A low level of copper detection at physiological pH using fluorescent probes is very important for in vitro applications, such as the detection of copper in water or urine, and in vivo applications, such as tracking the dynamic copper concentrations inside cells. Copper homeostasis is disrupted in neurological diseases like Alzheimer's disease, and copper forms aggregates with amyloid beta (Ab42) peptide, resulting in senile plaques in Alzheimer's brains. Therefore, a selective copper detector probe that can detect amyloid beta peptide-copper aggregates and decrease the aggregate size has potential uses in medicine. We have developed a series of Cu -selective low fluorescent to high fluorescent tri and tetradentate dentate ligands and conjugated them with a peptide ligand to amyloid-beta binding peptide to increase the solubility of the compounds and make the resultant compounds bind to Cu -amyloid aggregates. The copper selective compounds were developed using chemical scaffolds known to have high affinity and selectivity for Cu , and their conjugates with peptides were tested for affinity and selectivity towards Cu . The test results were used to inform further improvement of the next compound. The final Cu chelator-peptide conjugate we developed showed high selectivity for Cu and high fluorescence properties. The compound bound 1:1 to Cu ion, as determined from its Job's plot. Fluorescence of the ligand could be detected at nanomolar concentrations. The effect of this ligand on controlling Cu -Ab42 aggregation was studied using fluorescence assays and microscopy. It was found that the Cu -chelator-peptide conjugate efficiently reduced aggregate size and, therefore, acted as an inhibitor of Ab42-Cu aggregation. Since high micromolar concentrations of Cu are present in senile plaques, and Cu accelerates the formation of toxic soluble aggregates of Ab42, which are precursors of insoluble plaques, the developed hybrid molecule can potentially serve as a therapeutic for Alzheimer's disease.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2079-6374 2079-6374
DOI:	10.3390/bios14050247