The "amyloid cascade hypothesis," linking self-assembly of the amyloid-beta protein (Abeta) to the pathogenesis of Alzheimer's disease, has led to the emergence of inhibition of Abeta self-assembly as a prime therapeutic strategy for this currently unpreventable and devastating disease. The complexity of Abeta self-assembly, which involves multiple reaction intermediates related by nonlinear and interconnected nucleation and growth mechanisms, provides multiple points for inhibitor intervention. Although a number of small-molecule inhibitors of Abeta self-assembly have been identified, little insight has been garnered concerning the point at which these inhibitors intervene within the Abeta assembly process. In the current study, a julolidine derivative is identified as an inhibitor of Abeta self-assembly. To gain insight into the mechanistic action of this inhibitor, the inhibition of fibril formation from monomeric protein is assessed quantitatively and compared with the inhibition of two distinct mechanisms of growth for soluble Abeta aggregation intermediates. This compound is observed to significantly inhibit soluble aggregate growth by lateral association while having little effect on soluble aggregate elongation via monomer addition. In addition, inhibition of soluble Abeta aggregate association exhibits an IC(50) with a somewhat lower stoichiometric ratio than the IC(50) determined for inhibition of fibril formation from monomeric Abeta. This quantitative comparison of inhibition within multiple Abeta self-assembly assays suggests that this compound binds the lateral surface of on-pathway intermediates exhibiting a range of sizes to prevent their association with other aggregates, which is required for further assembly into mature fibrils.
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http://dx.doi.org/10.1124/mol.109.055301 | DOI Listing |
Bioorg Chem
January 2025
Henan Province Key Laboratory of New Opto-electronic Functional Materials, Anyang Normal University, Anyang, Henan 455000, China. Electronic address:
β-Amyloid (Aβ) peptides are believed as the diagnostic biomarkers and therapeutic targets of Alzheimer's disease (AD). Their complexes with copper ions can catalyze the generation of reactive oxygen species (ROS) to further promote neuronal death. Herein, we suggested that porphyrin-substituted phenylalanine-phenylalanine nanoparticles (TPP-FF NPs) could inhibit the aggregation of Aβ monomers, disassemble the fibrillar Aβ aggregates under light illumination, and depressing the Cu-induced generation of ROS.
View Article and Find Full Text PDFACS Nano
December 2024
Biophysical and Biomaterials Research Laboratory, Room 310, School of Life Sciences, Jawaharlal Nehru University, New Delhi 110067, India.
The neuromodulator 5-hydroxytryptamine, known as serotonin, plays a key regulatory role in the central nervous system and peripheral organs; however, several research revelations have indicated a direct link between the oxidation of serotonin and a plethora of detrimental consequences. Hence, the question of how several neuronal and non-neuronal complications originate via serotonin oxidation remains an important area of investigation. Here, we show the autoxidation-driven structural conversion of serotonin into hemolytic and cytotoxic amyloid-like nanoassemblies under physiological conditions.
View Article and Find Full Text PDFChem Sci
October 2024
Biochemistry and Structural Biology, Department of Chemistry, Lund University Lund Sweden
The self-assembly of amyloid-β peptide (Aβ) into fibrils and oligomers is linked to Alzheimer's disease (AD). Fibrillar aggregates in AD patient's brains contain several post-translational modifications, including phosphorylation at positions 8 and 26. These play a key role in modifying the aggregation propensity of Aβ, yet how they affect the mechanism of aggregation is only poorly understood.
View Article and Find Full Text PDFChem Commun (Camb)
November 2024
Institute of Theoretical and Computational Chemistry, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany.
The aggregation of amyloid-β (Aβ) peptides, particularly Aβ, plays a key role in Alzheimer's disease pathogenesis. In this study, we investigate how dimerisation transforms the free energy surface (FES) of the Aβ monomer when it interacts with another Aβ peptide. We find that the monomer FES is a structurally inverted funnel with a disordered state at the global minimum.
View Article and Find Full Text PDFInt J Nanomedicine
October 2024
Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Academy of Medical Science & Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, People's Republic of China.
Introduction: Alzheimer's disease (AD), a neurodegenerative condition, stands as the most prevalent form of dementia. Its complex pathological mechanisms and the formidable blood-brain barrier (BBB) pose significant challenges to current treatment approaches. Oxidative stress is recognized as a central factor in AD, underscoring the importance of antioxidative strategies in its treatment.
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