Scientists have discovered a neurotransmitter that could be a useful diagnostic tool and a potential drug target in patients with Alzheimer’s. The research carried out by Gong Chen, a professor of biology and Verne M. Willaman chair in Life Sciences at Penn State University, holds great promise in advancing knowledge of this condition, which kills more than 500,000 people each year. The study was published Friday in the journal Nature Communications.

In spite of being a widely researched condition, there are no specific drugs for the treatment of Alzheimer’s and previous attempts to develop drugs have proved unsuccessful. "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. For years, scientists attempted to create drugs to target amyloid beta, the main components of the amyloid plaques that form deposits and destroy neurons in the brain. But Chen’s research focused on other potential targets for drug and diagnostic use.

One such target is the neurotransmitter, called GABA (gamma-aminobutyric acid), of which the team found high concentrations in the brains of Alzheimer’s patients. Normally, GABA plays an important role in regulating the neurons in the central nervous system. But too much of it inhibits the neurons from firing up like they normally would when a healthy person is learning something new or remembering something already learned.

The researchers found excessively high concentrations of GABA in deformed cells called "reactive astrocytes," in a structure called dentate gyrus in the brain, which is a part of the hippocampus that contributes to the formation of new episodic memories. Astrocytes are star-shaped glial cells in the brain and spinal cord that are thought to play a number of major roles in maintaining the neural transmitters. In Alzheimer's patients, the astrocytes become hyperactive and get deformed.

It was around these deformed astrocytes, that the team found increased levels of GABA. "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. They then developed new methods to measure the concentrations of GABA in the brains of normal mice and transgenic mice models with Alzheimer’s (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 added.

Another important discovery was that of an astrocyte-specific GABA transporter, that releases the high concentration of GABA in reactive astrocytes. This transporter is a potential drug target to enhance GABA inhibition in the dentate gyrus. Inhibiting the transporter showed promising results, according to Chen. "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," he said.

Chen explained that although targeting amyloid proteins reduces amyloid plaques, the "other downstream alterations triggered by amyloid deposits" cannot be corrected in the same way. “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," Chen said.

 

Source: Chen G, Wu Z, Guo Z, Gearing M. Tonic inhibition in dentate gyrus impairs long-term potentiation and memory in an Alzhiemer’s disease model. Nature Communications. 2014.