JIJITANG2014-07-18 5:27 PM

Looking beyond brain plaque to treat Alzheimer’s

Researchers have found a new drug target to treat Alzheimer’s—one that also has the potential to serve as a diagnostic tool for the disease.

The recent failure in clinical trials of once-promising Alzheimer’s drugs under development by large pharmaceutical companies prompted the new study.

“Billions of dollars were invested in years of research leading up to the clinical trials of those Alzheimer’s drugs, but they failed the test after they unexpectedly worsened the patients’ symptoms,” says Gong Chen, a professor of biology at Penn State.

The research behind those drugs had targeted the long-recognized feature of Alzheimer’s brains: the sticky buildup of the amyloid protein known as plaques, which can cause neurons in the brain to die.

“The research of our lab and others now has focused on finding new drug targets and on developing new approaches for diagnosing and treating Alzheimer’s disease,” Chen explains.

“We recently discovered an abnormally high concentration of one inhibitory neurotransmitter in the brains of deceased Alzheimer’s patients,” Chen says.

GABA gateway
The neurotransmitter, called GABA (gamma-aminobutyric acid), showed up in deformed cells called “reactive astrocytes” in a brain structure called the dentate gyrus. This structure is the gateway to hippocampus, an area of the brain that is critical for learning and memory.

The GABA neurotransmitter was drastically increased in the deformed versions of the normally large, star-shaped “astrocyte” cells which, in a healthy individual, surround and support individual neurons in the brain.

“Our research shows that the excessively high concentration of the GABA neurotransmitter in these reactive astrocytes is a novel biomarker that we hope can be targeted in further research as a tool for the diagnosis and treatment of Alzheimer’s disease,” Chen says.

His lab also found that the high concentration of the GABA neurotransmitter in the reactive astrocytes is released through an astrocyte-specific GABA transporter, a novel drug target found in this study, to enhance GABA inhibition in the dentate gyrus.

With too much inhibitory GABA neurotransmitter, the neurons in the dentate gyrus are not fired up like they normally would be when a healthy person is learning something new or remembering something already learned.

Improved memory
Importantly, Chen says, “After we inhibited the astrocytic GABA transporter to reduce GABA inhibition in the brains of the AD mice, we found that they showed better memory capability than the control AD mice.

“We are very excited and encouraged by this result because it might explain why previous clinical trials failed by targeting amyloid plaques alone. One possible explanation is that while amyloid plaques may be reduced by targeting amyloid proteins, the other downstream alterations triggered by amyloid deposits, such as the excessive GABA inhibition discovered in our study, cannot be corrected by targeting amyloid proteins alone,” Chen says.

“Our studies suggest that reducing the excessive GABA inhibition to the neurons in the brain’s dentate gyrus may lead to a novel therapy for Alzheimer’s disease. An ultimate successful therapy may be a cocktail of compounds acting on several drug targets simultaneously.”

In addition to Chen, other members of the research team include Zheng Wu and Ziyuan Guo at Penn State and Marla Gearing at Emory University.

The National Institutes of Health and Penn State University’s Eberly College of Science Stem Cell Fund supported the study, which appears in Nature Communications.

Original Article:
《Tonic inhibition in dentate gyrus impairs long-term potentiation and memory in an Alzhiemer’s disease model》, Published on Journal《nature》in June 2014. 
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