CE can identify small molecules that selectively target soluble oligomers of amyloid β protein and display antifibrillogenic activity

  title={CE can identify small molecules that selectively target soluble oligomers of amyloid $\beta$ protein and display antifibrillogenic activity},
  author={Raffaella Colombo and Angelo Carotti and Marco Catto and Marco Racchi and Cristina Lanni and Laura Verga and Gabriele Caccialanza and Ersilia De Lorenzi},
Soluble and toxic oligomers of amyloid β (Aβ) protein have been identified as the true neurotoxic species involved in Alzheimer's disease and considering them as targets to inhibit Aβ aggregation might have a therapeutic value. We previously set up a CE method that enables the separation and quantification of transient oligomers of Aβ protein‐containing 42 amino acids (Aβ1–42) along the pathway leading to fibrils and we now demonstrate how this method can be successfully applied to examine the… 

Evidence that the Human Innate Immune Peptide LL-37 may be a Binding Partner of Amyloid-β and Inhibitor of Fibril Assembly

It is proposed that LL-37 and Aβ42 may be natural binding partners, which implies that balanced (or unbalanced) spatiotemporal expression of the two peptides could impact AD initiation and progression.

9,10‐Anthraquinone hinders β‐aggregation: How does a small molecule interfere with Aβ‐peptide amyloid fibrillation?

Investigation of the influence of two relatively similar tricyclic, planar compounds on the early phase of the aggregation of the Aβ heptapeptide segment H14QKLVFF20 shows evidence that structural perturbations by AQ can remarkably affect ordered oligomerization.

The Toxicity of Amyloid β Oligomers

It is shown that the aggregated oligomer causes membrane invagination, which is a precursor to the formation of pore structures and ion channels, and the molecule curcumin is a potential Aβ toxicity inhibitor as a β-sheet breaker by having a high propensity to interact with certain Aβ residues without binding to them.

Multifunctional cholinesterase and amyloid Beta fibrillization modulators. Synthesis and biological investigation.

In order to identify novel Alzheimer's modifying pharmacological tools, bis-tacrines bearing a peptide moiety for specific interference with surface sites of human acetylcholinesterase (hAChE) binding amyloid-beta (Aβ) proved to be inhibitors of hA ChE catalytic and noncatalytic functions and interfering with Aβ aggregation and with the Aβ self-oligomerization process.

Multitarget Therapeutic Leads for Alzheimer’s Disease: Quinolizidinyl Derivatives of Bi‐ and Tricyclic Systems as Dual Inhibitors of Cholinesterases and β‐Amyloid (Aβ) Aggregation

The time course of amyloid aggregation in the presence of the most active derivative revealed that these compounds might act as destabilizers of mature fibrils rather than mere inhibitors of fibrillization.

Modulation of Amyloid β-Induced Microglia Activation and Neuronal Cell Death by Curcumin and Analogues

The studied compounds exerted an anti-inflammatory effect on high molecular weight Aβ42O-stimulated microglia and possibly inhibitedmicroglia-mediated neuronal cell toxicity, and demonstrated antioligomeric activity during the process of in vitro A β42 aggregation.

Advances and Pitfalls in the Capillary Electrophoresis Analysis of Aggregates of Beta Amyloid Peptides

A novel and easy-to-run capillary electrophoresis with laser-induced fluorescence detection (CE-LIF) method for the specific analysis of fibrillar forms of A β aggregates obtained after in vitro incubation of Aβ 1-40 monomer is described.



Targeting the neurotoxic species in Alzheimer's disease: inhibitors of Aβ oligomerization

The anti‐amyloido‐genic and neuroprotective actions of some di‐ and tri‐substituted aromatic compounds described provide a basis for the development of novel small molecule Aβ inhibitors with potential applications in AD.

Certain Inhibitors of Synthetic Amyloid β-Peptide (Aβ) Fibrillogenesis Block Oligomerization of Natural Aβ and Thereby Rescue Long-Term Potentiation

The identification of small molecules that inhibit early Aβ oligomer formation and rescue LTP inhibition offers a rational approach for therapeutic intervention in Alzheimer's disease and highlights the utility of the cell-culture paradigm as a useful secondary screen for compounds designed to inhibit early steps in A β oligomerization under biologically relevant conditions.

Small Molecule Inhibitors of Aggregation Indicate That Amyloid β Oligomerization and Fibrillization Pathways Are Independent and Distinct*

The results indicate that oligomers are not an obligate intermediate in the fibril formation pathway and suggest that small molecule inhibitors are useful for clarifying the mechanisms underlying protein aggregation and may represent potential therapeutic agents that target fundamental disease mechanisms.

Amyloid β-protein: Monomer structure and early aggregation states of Aβ42 and its Pro19 alloform

The amyloid β-protein (Aβ) is a seminal neuropathic agent in Alzheimer's disease (AD). Recent evidence points to soluble Aβ oligomers as the probable neurotoxic species. Among the naturally occurring

Amyloid β-protein (Aβ) assembly: Aβ40 and Aβ42 oligomerize through distinct pathways

PICUP, size-exclusion chromatography, dynamic light scattering, circular dichroism spectroscopy, and electron microscopy have been combined to elucidate fundamental features of the early assembly of Aβ40 and Aβ42, demonstrating that A β42 assembly involves formation of several distinct transient structures that gradually rearrange into protofibrils.

Thioflavine T interaction with synthetic Alzheimer's disease β‐amyloid peptides: Detection of amyloid aggregation in solution

  • H. Levine
  • Biology, Chemistry
    Protein science : a publication of the Protein Society
  • 1993
Thioflavine T (ThT) associates rapidly with aggregated fibrils of the synthetic β/A4‐derived peptides β(1–28) and β(1–40), giving rise to a new excitation (ex) (absorption) maximum at 450 nm and

Analytical Method for β-Amyloid Fibrils Using CE-Laser Induced Fluorescence and Its Application to Screening for Inhibitors of β-Amyloid Protein Aggregation

A fast and sensitive analytical method for β-amyloid (Aβ) aggregates was developed by the combination of CE-laser induced fluorescence and the fluorescence reagent, thioflavine T.

Different Conformations of Amyloid β Induce Neurotoxicity by Distinct Mechanisms in Human Cortical Neurons

Various Aβ species may play relevant roles in AD, causing neurotoxicity by distinct non-overlapping mechanisms affecting neuronal function and viability over multiple time courses.

Controlling {beta}-amyloid oligomerization by the use of naphthalene sulfonates: trapping low molecular weight oligomeric species.

The stabilization of small oligomers of Abeta by the use of sulfonated hydrophobic molecules such as AMNS, 1-amino-5-naphthalene sulfonate; 1,8-ANS; 1-anilinonaphthalenes-8-sulfonate) and bis-ANS are described.