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

July 9, 2014
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). Credit: KIST

Research team in Korea has discovered that reactive astrocytes, which have been commonly observed in Alzheimer's patients, aberrantly and abundantly produce the chief inhibitory neurotransmitter GABA and release it through the Best1 channel. The released GABA strongly inhibits neighboring neurons to cause impairment in synaptic transmission, plasticity and memory. This discovery will open a new chapter in the development of new drugs for treating such diseases.

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 . 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 , synaptic transmission and memory in Alzheimer's disease model mice.

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.

A schematic diagram for the mechanism of memory impairment by reactive astrocytes in Alzheimer's disease. Credit: KIST

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 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.

The video will load shortly
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. 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."

Explore further: Rescue of Alzheimer's memory deficit achieved by reducing 'excessive inhibition'

Related Stories

Rescue of Alzheimer's memory deficit achieved by reducing 'excessive inhibition'

June 13, 2014
A new drug target to fight Alzheimer's disease has been discovered by a research team led by Gong Chen, a Professor of Biology and the Verne M. Willaman Chair in Life Sciences at Penn State University. The discovery also ...

Compounded outcomes associated with comorbid Alzheimer's disease, cerebrovascular disease

July 3, 2014
Researchers from the Sanders-Brown Center on Aging at the University of Kentucky have been able to confirm anecdotal information on patients with both Alzheimer's disease (AD) and cerebrovascular disease (CVD) using mouse ...

Neuroscientists find that limiting a certain protein in the brain reverses Alzheimer's symptoms in mice

April 15, 2014
Limiting a certain protein in the brain reverses Alzheimer's symptoms in mice, report neuroscientists at MIT's Picower Intitute for Learning and Memory.

Loss of memory in Alzheimer's mice models reversed through gene therapy

April 23, 2014
Alzheimer's disease is the leading cause of dementia and affects some 400,000 people in Spain alone. However, no effective cure has yet been found. One of the reasons for this is the lack of knowledge about the cellular mechanisms ...

Brain cell regeneration may alleviate symptoms of Alzheimer's disease

March 11, 2014
Alzheimer's disease is the most widespread degenerative neurological disorder in the world. Over five million Americans live with it, and one in three senior citizens will die with the disease or a similar form of dementia. ...

Cocoa extract may counter specific mechanisms of Alzheimer's disease

June 23, 2014
June 23) A specific preparation of cocoa-extract called Lavado may reduce damage to nerve pathways seen in Alzheimer's disease patients' brains long before they develop symptoms, according to a study conducted at the Icahn ...

Recommended for you

Newly discovered biomarkers may lead to promising diagnostic tool for Alzheimer's

July 28, 2017
Diagnosing Alzheimer's disease and determining a patient's prognosis is an inexact business, and that stands in the way of better personalized care and advances in treatment.

BACE-Inhibitor successfully tested in Alzheimer's animal model

July 28, 2017
The protein amyloid beta is believed to be the major cause of Alzheimer's disease. Substances that reduce the production of amyloid beta, such as BACE inhibitors, are therefore promising candidates for new drug treatments. ...

Scientists use new data mining strategy to spot those at high Alzheimer's risk

July 28, 2017
The push to develop treatments for Alzheimer's disease has been a promising and disappointing endeavor over the past two decades, yielding a greater understanding of the disease yet still failing to generate successful new ...

Lifestyle changes to stave off Alzheimer's? Hints, no proof

July 20, 2017
There are no proven ways to stave off Alzheimer's, but a new report raises the prospect that avoiding nine key risks starting in childhood just might delay or even prevent about a third of dementia cases around the world.

Blood test identifies key Alzheimer's marker

July 19, 2017
A new study led by researchers at Washington University School of Medicine in St. Louis suggests that measures of amyloid beta in the blood have the potential to help identify people with altered levels of amyloid in their ...

Steering an enzyme's 'scissors' shows potential for stopping Alzheimer's disease

July 19, 2017
The old real estate adage about "location, location, location" might also apply to the biochemical genesis of Alzheimer's disease, according to new research from the University of British Columbia.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.