P3-343: Homocysteine inhibits the enzymatic degradation of Aβ peptide

Abstract

Recent epidemiological and clinical data suggest that elevated serum homocysteine levels may increase the risk of developing Alzheimer's disease (AD), but the underlying mechanisms are unknown. We have recently created a new hyperhomocysteinemic transgenic/mutant model of AD and based on this work we determined that high homocysteine levels may be altering the enzymatic degradation of amyloid-β-peptide (Aβ). We used a cell culture and an animal model to explore the manner in which high levels of homocysteine may alter the development of AD neuropathology. Also, by measuring the ability of degrading a fluorogenic substrate by recombinant IDE enzyme we gathered evidence in vitro and in vivo suggesting that homocysteine may inhibit IDE activity. Our data shows that homocysteine markedly inhibited IDE activity in a dose dependent manner in cells and tissue models. We demonstrate key alterations in the conformation of the enzyme by non-competitive inhibition that alters its activity. This work contributes to the mechanism whereby homocysteine, a known risk factor for AD, can directly impact the progression of the neuropathology AD.