S-Nitrosylation of insulin degrading enzyme in Alzheimer's disease

AKHTAR MW; SANZ BLASCO S; DOLATABADI N; CHON K; PARKER J; AMBASUDHAN R; SOUSSOU R; MCKERCHER SR; NAKAMURA T; LIPTON SA

Washington DC

Congreso; SfN 2014; 2014

Alzheimer?s disease (AD) is the most common form of dementia in the elderly.Cognitive dysfunction in AD is best correlated with synaptic injury, especially inthe hippocampus and neocortex. AD is characterized by the presence ofextracellular amyloid plaques rich in amyloid-beta (Aβ) peptides and intracellularneurofibrillary tangles of hyperphosphorylated Tau protein. Work over the lastdecade suggests that in most cases oligomeric Aβ is the toxic species to neuronsrather than the plaques themselves. During AD onset, Aβ levels increase,apparently due to excessive production as well as decreased catabolism. Insulindegrading enzyme (IDE), a zinc-metalloproteinase, is one of the enzymes thatdegrades Aβ and plays an important role in maintaining the level of Aβ in thebrain. Here we report that IDE can be S-nitrosylated upon exposure to the nitricoxide (NO) donor S-nitrosocysteine (SNOC) in cortical neuronal cultures, whichleads to inhibition of its Aβ-degrading activity. Moreover, we found that exposureof rat cortical cultures or hippocampal slices to oligomeric Aβ, known to causenitrosative stress via increased NO production, leads to an increase in Snitrosylationof IDE (forming SNO-IDE). Furthermore, we observed an increase inSNO-IDE in human AD postmortem brains compared to age-matched controls.Taken together, our results suggest that S-nitrosylation of IDE compromises itsactivity in AD brain.