Maintenance of Glyoxalase Activity Prevents Alzheimer's Disease in a Mouse Model

Methylglyoxal and glyoxal result from glycolysis and normal metabolic pathways. Since methylglyoxal is highly cytotoxic, the body developed several detoxification mechanisms. One of these is the glyoxalase system. Methylglyoxal reacts with glutathione (GSH) to form a hemithioacetal. This is converted into S-D-lactoyl-glutathione by glyoxalase I, and then further metabolized into D-lactate by glyoxalase II. Glyoxalase is overexpressed in the early and middle-stages of Alzheimer’s disease, but depletion of glutathione in the Alzheimer’s-afflicted brain inhibits its ability to function.

In the current study, investigators at the University of Minnesota (Minneapolis, USA) evaluated the effectiveness of the synthetic cofactor of glyoxalase, psi-GSH (psi-glutathione), in treating the APP/PS1 transgenic mouse model of Alzheimer's disease.

They reported in the November 19, 2012, online edition of the journal ACS Chemical Neuroscience that psi-GSH administration prevented the development of memory impairment as demonstrated by the animals' retention of the ability to negotiate a maze. Amyloid beta deposition and oxidative stress indicators were drastically reduced in the psi-GSH treated APP/PS1 mice, while the compound showed no discernible toxicity at doses as high as two grams/kilogram.

“While most other drugs under development and on the market attempt to slow down or reverse the Alzheimer’s processes, our approach strikes at a root cause by enabling the brain itself to fight the disease at a very early stage,” said first author Dr. Robert Vince, professor of medicinal chemistry at the University of Minnesota. “As is the case with all drug development, these studies need to be replicated in human patients before coming to any firm conclusions.”

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