Amyloid-beta protein 40 (3-nitrotyrosine modified) (3NTyr-Aβ1-40)

Amyloid-beta 1-40 (Aβ1-40) is a 40-amino acid peptide derived from the proteolytic processing of the amyloid precursor protein (APP) by the enzymes beta-secretase and gamma-secretase (UniProt P05067 [https://www.uniprot.org/uniprotkb/P05067/entry]). While Aβ1-40 is the most abundant soluble isoform in the brain, its misfolded and post-translationally modified forms, specifically 3-nitrotyrosine-modified Aβ (3NTyr-Aβ), are highly associated with Alzheimer's disease pathology (Kummer et al., 2011 [https://doi.org/10.1038/nature10669]). Nitration of the tyrosine residue at position 10 occurs under conditions of oxidative stress, which is a hallmark of neurodegeneration (PubMed PMID: 22170609 [https://pubmed.ncbi.nlm.nih.gov/22170609/]). This modification significantly accelerates the aggregation of Aβ monomers into toxic oligomers and insoluble plaques, with 3NTyr-Aβ acting as a potent "seed" for further protein deposition (Nature, 2011). Therapeutic strategies targeting these specific monomers, such as the monoclonal antibody solanezumab, aim to sequester the peptide in its soluble state to prevent the formation of neurotoxic aggregates (AlzForum [https://www.alzforum.org/therapeutics/solanezumab]). However, clinical trials have faced challenges, highlighting the complexity of targeting specific Aβ species without causing adverse effects like amyloid-related imaging abnormalities (ARIA). Research continues into whether specifically targeting nitrated or other modified forms of Aβ can provide a more precise and effective intervention for Alzheimer's disease.

Other names

3-nitrotyrosine amyloid-betaNitrated AβMisfolded Aβ1-40 monomernAβAmyloid-beta 1-40Abeta 40

Sequestration of soluble amyloid-beta monomers to prevent their aggregation into neurotoxic oligomers and fibrils, often referred to as the "peripheral sink" hypothesis when clearance occurs via the blood-brain barrier (AlzForum [https://www.alzforum.org/therapeutics/solanezumab]).