Discovery of new drug targets for memory impairment in Alzheimer's disease

In the behavioral test, the team used the fact that mice tend to prefer dark places. If a mouse experiences an electric shock in a dark place, it will remember this event and avoid dark places from then on. However, a mouse with modeled Alzheimer's disease cannot remember if such shock is related to dark places and keeps going back to dark places. The team demonstrated that treating these mice with a MAO-B inhibitor fully recovered the mice's memory. The selegiline**** is currently used in Parkinson's disease as an adjunct therapy and considered as a one of best promising medicine for MAO-B inhibitor. But it has been previously shown to be less effective in Alzheimer's disease.

The team proved that selegiline is effective for a short time, but when it is used in long term, it loses its efficacy in Alzheimer's disease model mice. When treated for 1 week, selegiline brought the neuronal firing to a normal level. But when it was treated for 2 and 4 weeks, neuronal firing came back to the levels of untreated mice. From these results, the team proposed that there is a pressing need for a new drug that has long lasting effects.

This is a movie showing how the reactive astrocytes in the brains of Alzheimer's disease model produce the inhibitory transmitter GABA by the enzyme MAO-B and release GABA through the Bestrophin-1 channel to suppress normal information flow during synaptic transmission.

(Photo Credit: ©KIST)

Dr. C. Justin Lee said, "From this study, we reveal the novel mechanism of how Alzheimer's patients might lose their memory. We also propose new therapeutic targets, which include GABA production and release mechanisms in reactive astrocytes for treatment of Alzheimer's disease. Furthermore, we provide a stepping stone for the development of MAO-B inhibitors with long lasting efficacy."

This is a schematic diagram for the mechanism of memory impairment by reactive astrocytes in Alzheimer's disease.

(Photo Credit: ©KIST)

Confocal microscopy images are shown of the hippocampus from normal and Alzheimer's disease model mice. Astrocytes (green) become reactive (arrow) around amyloid plaques (blue) and have as much GABA (red) as GABAergic neurons (arrowhead).

(Photo Credit: ©KIST)

Source: Korea Institute of Science and Technology