In
Alzheimer's disease (AD), in aging, and under conditions of oxidative stress, the levels of reactive carbonyl compounds continuously increase. Accumulating carbonyl levels might be caused by an impaired enzymatic detoxification system. The major dicarbonyl detoxifying system is the glyoxalase system, which removes
methylglyoxal in order to minimize cellular impairment. Although a reduced activity of
glyoxalase I was evident in aging brains, it is not known how raising the intracellular
methylglyoxal level influences neuronal function and the phosphorylation pattern of
tau protein, which is known to be abnormally hyperphosphorylated in AD. To simulate a reduced
glyoxalase I activity, we applied an inhibitor of
glyoxalase I, p-bromobenzylglutathione cyclopentyl diester (pBrBzGSCp(2)), to SH-SY5Y
neuroblastoma cells to induce chronically elevated
methylglyoxal concentrations. We have shown that 10 microM pBrBzGSCp(2) leads to a fourfold elevation of the
methylglyoxal level after 24 hr. In addition,
glyoxalase I inhibition leads to reduced cell viability, strongly retracted
neuritis, increase in [Ca(2+)](i), and activation of
caspase-3. However, pBrBzGSCp(2) did not lead to tau "hyper"-phosphorylation despite activation of
p38 mitogen-activated protein kinase and c-Jun NH(2)-terminal
kinase but rather activated
protein phosphatases 2 and induced tau dephosphorylation at the Ser(202)/Thr(205) and Ser(396)/Ser(404)
epitopes. Preincubation with the carbonyl scavenger
aminoguanidine prevented tau dephosphorylation, indicating the specific effect of
methylglyoxal. Also, pretreatment with the inhibitor
okadaic acid prevented tau dephosphorylation, indicating that
methylglyoxal activates PP-2A. In summary, our data suggest that a reduced
glyoxalase I activity mimics some changes associated with neurodegeneration, such as neurite retraction and apoptotic cell death.