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PUBLIC RELEASE DATE:
8-Jul-2014

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Contact: Dr. C. Justin Lee
cjl@kist.re.kr
82-102-825-7128
Korea Institute of Science and Technology

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

Scientists investigate the cause of memory impairment through GABA from reactive astrocytes

VIDEO: 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...

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Alzheimer's disease, which is the most common cause of dementia, is fatal and currently, there is no cure. In Alzheimer's disease, brain cells are damaged and destroyed, leading to devastating memory loss. It is reported that 1 in 8 Americans aged 65 or over have Alzheimer's disease. In 2011, 7,600 elderly people with dementia lost their way back home and became homeless in Korea. However, to date, there has been no clear understanding of the mechanisms underlying dementia in Alzheimer's disease. So far, neuronal death is the only proposed mechanism available in scientific literature.

The research team led by Dr. C. Justin Lee at Korea Institute of Science and Technology (KIST) and Dr. Daesoo Kim(KAIST) discovered that reactive astrocytes* in the brains of Alzheimer's disease model mice produce the inhibitory transmitter GABA** by the enzyme Monoamine oxidase B***(MAO-B) and release GABA through the Bestrophin-1 channel to suppress normal information flow during synaptic transmission. Based on this discovery, the team was able to reduce the production and release of GABA by inhibiting MAO-B or Bestrophin-1, and successfully ameliorate impairments in neuronal firing, synaptic transmission and memory in Alzheimer's disease model mice.

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

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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.

IMAGE: 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)...

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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."

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This research has been conducted at the WCI Center for Functional Connectomics, Brain Science Institute, Korea Institute of Science and Technology (KIST) in collaboration with the domestic and international research teams including KAIST. This research was funded by the Ministry of Science ICT and Future Planning (MSIP) and the National Research Foundation of Korea (NRF) as part of the World Class Institute Project and the KIST Brain Science Institute's Flagship Project.

*Astrocytes

Astrocytes are the most abundant cell type of the human brain. They perform many functions, including biochemical support of endothelial cells that form the blood–brain barrier, provision of nutrients to the nervous tissue, maintenance of extracellular ion balance and a role in the repair and scarring process of the brain and spinal cord following traumatic injury.

** gamma-Aminobutyric acid (GABA)

γ-Aminobutyric acid or GABA is the chief inhibitory neurotransmitter in the mammalian central nervous system. It plays a role in regulating neuronal excitability throughout the nervous system. In humans, GABA is also directly responsible for the regulation of muscle tone

*** Monoamine oxidase B (MAOB)

Monoamine oxidase B, also known as MAOB, is an enzyme that in humans is encoded by the MAOB gene. The protein encoded by this gene belongs to the flavin monoamine oxidase family. It is an enzyme located in the outer mitochondrial membrane. It catalyzes the oxidative deamination of biogenic and xenobiotic amines and plays an important[citation needed] role in the metabolism of neuroactive and vasoactive amines in the central nervous system and peripheral tissues.

**** Selegiline

Selegiline is a drug used for the treatment of early-stage Parkinson's disease, depression and dementia. In normal clinical doses it is a selective irreversible MAO-B inhibitor.



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