Post-translational modifications of beta-amyloid alter its transport in the blood-brain barrier in vitro model.

ABSTRACT

One of the hallmarks of Alzheimer's disease (AD) is the accumulation of beta-amyloid peptide (Aß) leading to formation of soluble neurotoxic Aß oligomers and insoluble amyloid plaques in various parts of the brain. Aß undergoes post-translational modifications that alter its pathogenic properties. Aß is produced not only in brain, but also in the peripheral tissues. Such Aß, including its post-translationally 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 Aß across the blood-brain barrier (BBB) has not been investigated. Here, we used a transwell BBB model as a controlled environment for permeability studies. We found that Aß42 containing isomerized Asp7 residue (iso-Aß42) and Aß42 containing phosphorylated Ser8 residue (pS8-Aß42) crossed the BBB better than unmodified Aß42, which correlated with different contribution of endocytosis mechanisms to the transport of these isoforms. Using microscale thermophoresis, we observed that RAGE binds to iso-Aß42 an order of magnitude weaker than to Aß42. Thus, post-translational modifications of Aß 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.