4-4-difluoro-4-bora-3a-4a-diaza-s-indacene and Alzheimer-Disease

Amyloid formation plays a major role in a number of neurodegenerative diseases, including Alzheimer's disease. Amyloid-β peptides (Aβ) are one of the primary markers associated with this pathology. Aβ aggregates exhibit a diverse range of morphologies with distinct pathological activities. Recognition of the Aβ aggregates by using small molecule-based probes and sensors should not only enhance understanding of the underlying mechanisms of amyloid formation, but also facilitate the development of therapeutic strategies to interfere with amyloid neurotoxicity. BODIPY (boron dipyrrin) dyes are among the most versatile small molecule fluorophores. BODIPY scaffolds could be functionalized to tune their photophysical properties to the desired ranges as well as to adapt these dyes to various types of conditions and environments. Thus, BODIPY dyes could be viewed as unique platforms for the design of probes and sensors that are capable of detecting and tracking structural changes of various Aβ aggregates. This review summarizes currently available examples of BODIPY dyes that have been used to investigate conformational changes of Aβ peptides, self-assembly processes of Aβ, as well as Aβ interactions with various molecules.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Biosensing Techniques; Boron Compounds; Fluorescent Dyes; Humans; Peptide Fragments

With accumulating evidence suggesting that amyloid-β (Aβ) deposition is a good diagnostic biomarker for Alzheimer's disease (AD), the discovery of active Aβ probes has become an active area of research. Among the existing imaging methods, optical imaging targeting Aβ aggregates (fibrils or oligomers), especially using near-infrared (NIR) fluorescent probes, is increasingly recognized as a promising approach for the early diagnosis of AD due to its real time detection, low cost, lack of radioactive exposure and high-resolution. In the past decade, a variety of fluorescent probes have been developed and tested for efficiency in vitro, and several probes have shown efficacy in AD transgenic mice. This review classifies these representative probes based on their chemical structures and functional modes (dominant solvent-dependent mode and a novel solvent-independent mode). Moreover, the pharmaceutical characteristics of these representative probes are summarized and discussed. This review provides important perspectives for the future development of novel NIR Aβ diagnostic probes.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Benzothiazoles; Boron Compounds; Curcumin; Fluorescent Dyes; Humans; Optical Imaging; Stilbenes; Thiazoles; Thiophenes

Singlet oxygen (

Topics: Alzheimer Disease; Boron; Humans; Neuronal Outgrowth; Photosensitizing Agents; Protein Aggregates; Ruthenium; Singlet Oxygen; tau Proteins

Soluble amyloid β (Aβ) aggregates, suggested to be the most toxic forms of Aβ, draw attention as therapeutic targets and biomarkers of Alzheimer's disease (AD). As soluble Aβ aggregates are transient and diverse, imaging their diverse forms

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Boron Compounds; Brain; Fluorescent Dyes; Mice; Mice, Transgenic; Optical Imaging; Plaque, Amyloid

Neurofibrillary tangles (NFTs), which are composed of abnormally hyperphosphorylated Tau, are one of the main pathologic hallmarks of Alzheimer's disease and other tauopathies. The fluorescent imaging probes currently used to target NFTs cannot distinguish them well from β-amyloid plaques, thus limiting their utility to diagnose diseases. Here, we developed a fused cycloheptatriene-BODIPY derivative (

Topics: Alzheimer Disease; Animals; Brain; Disease Models, Animal; Fluorescent Dyes; Mice; Mice, Transgenic; Molecular Docking Simulation; Neurofibrillary Tangles; Plaque, Amyloid; tau Proteins; Tauopathies

Amyloid formation and the deposition of the amyloid-β peptide are hallmarks of Alzheimer's disease pathogenesis. Immunotherapies using anti-amyloid-β antibodies have been highlighted as a promising approach for the prevention and treatment of Alzheimer's disease by enhancing microglial clearance of amyloid-β peptide. However, the efficiency of antibody delivery into the brain is limited, and therefore an alternative strategy to facilitate the clearance of brain amyloid is needed. We previously developed an artificial photo-oxygenation system using a low molecular weight catalytic compound. The photocatalyst specifically attached oxygen atoms to amyloids upon irradiation with light, and successfully reduced the neurotoxicity of aggregated amyloid-β via inhibition of amyloid formation. However, the therapeutic effect and mode of actions of the photo-oxygenation system in vivo remained unclear. In this study, we demonstrate that photo-oxygenation facilitates the clearance of aggregated amyloid-β from the brains of living Alzheimer's disease model mice, and enhances the microglial degradation of amyloid-β peptide. These results suggest that photo-oxygenation may represent a novel anti-amyloid-β strategy in Alzheimer's disease, which is compatible with immunotherapy.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Boron Compounds; Brain; Disease Models, Animal; Humans; Mice; Microglia; Phototherapy; Protein Aggregates

In this study, a series of organo difluoroboron probes with a BF2 benzamide moiety was designed, prepared and evaluated. Among them, 2c displayed the best optical and biological properties, and may be used as a useful near-infrared fluorescent probe for the detection of Aβ plaques and neurofibrillary tangles in AD.

Topics: Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Animals; Benzamides; Biological Transport; Biosensing Techniques; Boron Compounds; Disease Models, Animal; Female; Fluorescent Dyes; Hippocampus; Humans; Hydrophobic and Hydrophilic Interactions; Male; Mice; Optical Imaging; Presenilin-1; Protein Binding; Protein Conformation; Spectrometry, Fluorescence; Spectroscopy, Near-Infrared; tau Proteins

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Boron Compounds; Brain; Disease Models, Animal; Fluorescent Dyes; Male; Mice; Mice, Transgenic; Plaque, Amyloid; Spectrometry, Fluorescence

A straightforward functionalization of BODIPY dyes via incorporation of a triazole moiety produced fluorescent dyes that were capable of distinguishing between secondary structure conformations of soluble oligomeric species of Abeta1-42 peptide. Small concentrations of the dyes, relative to Abeta1-42, provided up to an 8-fold and 35-fold fluorescence increase in the presence of the unordered and ordered, beta-sheet-rich conformations of soluble Abeta1-42 oligomers, respectively. These triazole-containing dyes could prove to be useful probes for monitoring amyloid conformational transitions in vitro.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Boron Compounds; Fluorescent Dyes; Humans; Peptide Fragments; Protein Conformation; Triazoles

We have developed a new fluorescent binuclear Zn(II) complex for the detection of neurofibrillary tangles (NFTs) of hyperphosphorylated tau proteins, a representative hallmark of Alzheimer's disease (AD). The probe 1 incorporates a fluorescent BODIPY unit and two Zn(II)-2,2'-dipicolylamine (Dpa) complexes as a binding site for phosphorylated amino acid residues. Using fluorescence titration to evaluate the binding and sensing properties of 1 toward several phosphorylated peptide segments derived from hyperphosphorylated tau protein, we found that 1 binds preferentially to peptides presenting phosphorylated groups at the i and i+4 positions with dissociation constants (K(d)) in the micromolar range. Fluorescence titration with an artificially prepared aggregate of the phosphorylated tau protein (p-Tau) revealed that 1 binds strongly to p-Tau (EC(50) = 9 nM). In contrast, the interactions of 1 were weaker toward artificially prepared aggregates of the nonphosphorylated tau protein (n-Tau; EC(50) = 80 nM) and Abeta(1-42) fibrils (EC(50) = 650 nM). Histological imaging of a hippocampus tissue section obtained from an AD patient revealed that 1 fluorescently visualizes deposits of NFTs and clearly discriminates between NFTs and the amyloid plaques assembled from amyloid-beta peptides, confirming our strategy toward the rational design of a molecular probe for the selective fluorescence detection of NFTs in brain tissue sections.

Topics: Alzheimer Disease; Boron Compounds; Brain; Hippocampus; Humans; Molecular Probe Techniques; Neurofibrillary Tangles; Phosphorylation; tau Proteins; Zinc

GM1 ganglioside-bound amyloid beta-protein (GM1-Abeta), found in brains exhibiting early pathological changes of Alzheimer's disease (AD) plaques, has been suggested to accelerate amyloid fibril formation by acting as a seed. We have previously found using dye-labeled Abeta that Abeta recognizes a GM1 cluster, the formation of which is facilitated by cholesterol [Kakio, A., Nishimoto, S., Yanagisawa, K., Kozutsumi, Y., and Matsuzaki, K. (2001) J. Biol. Chem. 276, 24985-24990]. In this study, we investigated the ganglioside species-specificity in its potency to induce a conformational change of Abeta, by which ganglioside-bound Abeta acts as a seed for Abeta fibrillogenesis, using a major ganglioside occurring in brains (GM1, GD1a, GD1b, and GT1b) in raft-like membranes composed of cholesterol and sphingomyelin. Abeta recognized ganglioside clusters, the density of which increased with the number of sialic acid residues. Interestingly, however, mixing of gangliosides inhibited cluster formation. In contrast, the affinities of the protein for the clusters were similar irrespective of lipid composition and of the order of 10(6) M(-)(1) at 37 degrees C. Abeta underwent a conformational transition from an alpha-helix-rich structure to a beta-sheet-rich structure with the increase in protein density on the membrane. Ganglioside-bound Abeta proteins exhibited seeding abilities for amyloid formation. GM1-Abeta exhibited the strongest seeding potential, especially under beta-sheet-forming conditions. This study suggested that lipid composition including gangliosides and cholesterol strictly controls amyloid formation.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Binding Sites; Boron Compounds; Cattle; Coumarins; Fluorescent Dyes; G(M1) Ganglioside; Humans; Liposomes; Membrane Microdomains; Peptide Fragments; Protein Structure, Secondary

GM1 ganglioside-bound amyloid beta-protein (GM1/Abeta), found in brains exhibiting early pathological changes of Alzheimer's disease (AD) including diffuse plaques, has been suggested to be involved in the initiation of amyloid fibril formation in vivo by acting as a seed. To elucidate the molecular mechanism underlying GM1/Abeta formation, the effects of lipid composition on the binding of Abeta to GM1-containing lipid bilayers were examined in detail using fluorescent dye-labeled human Abeta-(1-40). Increases in not only GM1 but also cholesterol contents in the lipid bilayers facilitated the binding of Abeta to the membranes by altering the binding capacity but not the binding affinity. An increase in membrane-bound Abeta concentration triggered its conformational transition from helix-rich to beta-sheet-rich structures. Excimer formation of fluorescent dye-labeled GM1 suggested that Abeta recognizes a GM1 "cluster" in membranes, the formation of which is facilitated by cholesterol. The results of the present study strongly suggested that increases in intramembrane cholesterol content, which are likely to occur during aging, appear to be a risk factor for amyloid fibril formation.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Binding Sites; Binding, Competitive; Boron Compounds; Cell Line; Cholesterol; Coumarins; Fluorescent Dyes; G(M1) Ganglioside; Humans; Lipid Bilayers; Protein Binding; Protein Conformation; Spectrometry, Fluorescence