Salt, Acidic Conditions Promote Alzheimer’s Hallmark Amyloidosis, Study Shows
Salt together with acidic conditions can change the 3D structure of the beta2-microglobulin protein and promote the formation of amyloid fibrils — a hallmark of Alzheimer’s disease.
The study, “Conformational properties relevant to the amyloidogenicity of beta2-migroglobulin analyzed using pressure and salt dependent chemical shift data” was published in the Journal of Physical Chemistry.
Amyloidosis is a condition characterized by the accumulation of inappropriately folded amyloid fibrils — long, abnormal protein fibrils — in tissues or organs, disrupting their normal function. The condition is also found in other diseases, including type 2 diabetes, and in people with kidney failure who have been on long-term dialysis (called dialysis-related amyloidosis).
Beta2-microglobulin is a well-studied protein known to cause amyloidosis. When it is not cleared from circulation because of reduced renal function, it leads to the formation of amyloid fibrils. Understanding the biochemical processes by which beta2-microglobulin gives rise to amyloid fibrils would open the possibility for new therapeutic approaches.
A team of Japanese researchers explored the effect of salt on the 3D arrangement of the beta2-microglobulin protein. Salt, or sodium chloride, is essential to how proteins organize their structure.
The researchers applied a technique called high pressure nuclear magnetic spectroscopy (NMR) to analyze how beta2-microglobulin structure changed with increasing doses of salt.
Previous studies have shown that acidic conditions (defined by a pH below 6) promote beta2-microglobulin aggregation into amyloid fibrils. Now, researchers observed that adding salt (at a concentration of 100 milimolar) led to an expansion of the beta2-microglobulin from 2.35 nanometers (nm) without salt to 2.80 nm.
Moreover, salt affected how the initial part of the protein, called N-terminal, interacted with other regions of beta2-microglobulin. This likely resulted from the exclusion of the N-terminal region from the central region of the protein, called the hydrophobic cluster region.
Most importantly, this led to the formation of a rigid core within the protein that is necessary for amyloid formation.
These results suggest that the N-terminal of this protein is able to inhibit amyloid formation and can become a potential target to block amyloidosis.