The Herp protein pathway is not involved in the pro-amyloidogenic effect of hyperhomocysteinemia

Diet-induced high circulating levels of homocysteine, also known as hyper-homocysteinemia (HHcy), is associated with an acceleration of Alzheimer's disease-like amyloidosis. Herp is a homocysteine-responsive stress protein, which has been shown to increase the formation of amyloid-beta (Abeta) via interaction with presenilins in vitro. The aim of our paper was to investigate the functional role that Herp plays in HHcy-induced amyloidosis. Amyloidosis secondary to diet-induced HHcy in Tg2576 mice is associated with an increase of Herp protein and mRNA levels. By contrast, no other stress-related proteins are altered by the same diet regimen. Compared to wild type animals, brains from a genetically induced HHcy mouse model did not manifest any significant change in Herp levels. Cells stably over-expressing human AbetaPP Swedish mutant incubated with high levels of homocysteine had an increase in Abeta formation, but no change in Herp level. Finally, over-expression of Herp did not result in any significant modification of Abeta levels. We conclude that the Herp protein pathway is unlikely to be directly involved in the pro-amyloidotic effect of HHcy.