AUTHOR=Varshavskaya Kseniya B. , Petrushanko Irina Yu , Mitkevich Vladimir A. , Barykin Evgeny P. , Makarov Alexander A. TITLE=Post-translational modifications of beta-amyloid alter its transport in the blood-brain barrier in vitro model JOURNAL=Frontiers in Molecular Neuroscience VOLUME=Volume 17 - 2024 YEAR=2024 URL=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2024.1362581 DOI=10.3389/fnmol.2024.1362581 ISSN=1662-5099 ABSTRACT=One of the hallmarks of Alzheimer's disease (AD) is the accumulation of beta-amyloid peptide (Aβ) leading to formation of soluble neurotoxic Aβ oligomers and insoluble amyloid plaques in various parts of the brain. Aβ undergoes post-translational modifications that alter its pathogenic properties. Aβ is produced not only in brain, but also in the peripheral tissues. Such Aβ, including its posttranslationally modified forms, can enter the brain from circulation by binding to RAGE and contribute to the pathology of AD. However, the transport of modified forms of Aβ across the bloodbrain barrier (BBB) has not been investigated. Here, we used a transwell BBB model as a controlled environment for permeability studies. We found that Aβ 42 containing isomerized Asp7 residue (iso-Aβ 42 ) and Aβ 42 containing phosphorylated Ser8 residue (pS8-Aβ 42 ) crossed the BBB better than unmodified Aβ 42 , which correlated with different contribution of endocytosis mechanisms to the transport of these isoforms. Using microscale thermophoresis, we observed that RAGE binds to iso-Aβ 42 an order of magnitude weaker than to Aβ 42 . Thus, post-translational modifications of Aβ increase the rate of its transport across the BBB and modify the mechanisms of the transport, which may be important for AD pathology and treatment.