Discovery of abnormal GABA levels may lead to improvements in diagnosing, treating Alzheimer’s disease

Drugs focusing only on plaque buildup have failed; reducing GABA inhibition may also be needed
June 18, 2014

A new drug target to fight Alzheimer’s disease has been discovered by a research team led by Gong Chen at Penn State that also has potential for development as a novel diagnostic tool for Alzheimer’s disease. This image shows a microscopic view of the high concentration (red) of gamma-aminobutyric acid (GABA) in the reactive astrocytes (green) in the human brain with Alzheimer’s disease (GFAP). (Credit: Gong Chen lab, Penn State University)

A new drug target to fight Alzheimer’s disease has been discovered by a Penn State research team.

The discovery also has potential for development as a novel diagnostic tool for Alzheimer’s disease, which is the most common form of dementia and one for which no cure has yet been found.

A scientific paper describing the discovery was published in Nature Communications on June 13.

The research team is led by Gong Chen, a professor of biology and the Verne M. Willaman Chair in Life Sciences.

Why Alzheimer’s drugs have failed

Chen’s research was motivated by the recent failure in clinical trials of once-promising Alzheimer’s drugs being developed by large pharmaceutical companies.

“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,” Chen said.

The research behind those drugs had targeted the long-recognized feature of Alzheimer’s patients’ 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 explained.

High concentration of GABA neurotransmitter in brains of deceased Alzheimer’s patients

Human hippocampal tissue from AD patients showed higher GABA content in reactive astrocytes. GABA immunostaining (red) in the molecular layer of the dentate gyrus in human hippocampal tissue. Control human astrocytes showed little GABA staining (top row), whereas astrocytes from AD patients showed significant amount of GABA staining (arrow). Arrowhead points to GABAergic neuron. (Credit: Zheng Wu et al./Nature Communications)

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

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

Working model. Control (WT, or wild type) animals (green) have normal level of GABA and other substances in astrocytes and dentate granule cells, there is significant long-term potentiation (LTP) (learning ability) in the dentage gyrus, and animals have normal cognitive functions.
Mouse models for AD (5xFAD) (red) show abnormally high level of GABA and other substances in the reactive astrocytes. The tonic inhibition is significantly enhanced, and LTP in the dentate gyrus is suppressed. Animals display learning and memory deficits. (Credit: Zheng Wu et al./Nature Communications)

Chen’s team found that 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 said.

Chen’s team developed new analysis methods to evaluate neurotransmitter concentrations in the brains of normal and genetically modified mouse models for Alzheimer’s disease (AD mice).

“Our studies of AD mice showed that the high concentration of the GABA neurotransmitter in the reactive astrocytes of the dentate gyrus correlates with the animals’ poor performance on tests of learning and memory,” Chen said.

His lab also found that the high concentration of the GABA neurotransmitter in the reactive astrocytes is released through an astrocyte-specific GABA transporter 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.

Importantly, Chen said, “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. 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 postdoctoral scholar Zheng Wu and graduate researcher Ziyuan Guo at Penn State and Marla Gearing at Emory University.

This research received support from the National Institutes of Health and Penn State University’s Eberly College of Science Stem Cell Fund.

Abstract of Nature Communications paper

Amyloid plaques and tau tangles are common pathological hallmarks for Alzheimer’s disease (AD); however, reducing Aβ production failed to relieve the symptoms of AD patients. Here we report a high GABA (γ-aminobutyric acid) content in reactive astrocytes in the dentate gyrus (DG) of a mouse model for AD (5xFAD) that results in increased tonic inhibition and memory deficit. We also confirm in human AD patient brains that dentate astrocytes have a high GABA content, suggesting that high astrocytic GABA level may be a novel biomarker and a potential diagnostic tool for AD. The excessive GABA in 5xFAD astrocytes is released through an astrocyte-specific GABA transporter GAT3/4, and significantly enhances tonic GABA inhibition in dentate granule cells. Importantly, reducing tonic inhibition in 5xFAD mice rescues the impairment of long-term potentiation (LTP) and memory deficit. Thus, reducing tonic GABA inhibition in the DG may lead to a novel therapy for AD.