Possible New Alzheimer's Drug Target Discovered

Gong Chen lab, Penn State University

A team of researchers based at Penn State University has discovered a potential new drug target for Alzheimer’s disease that could also lead to the development of a novel diagnostic tool for this disease. The study has been published in Nature Communications.

Alzheimer’s disease is the most common form of dementia that is characterized by a progressive decline in cognitive function. Brains of Alzheimer’s patients experience massive injury and death of neurons. This atrophy begins in the region of the brain involved in learning and memory, called the hippocampus, and then spreads to other areas.

Although there remains some uncertainty about the mechanisms behind disease progression, it is associated with a build-up of two different types of protein in the brain; amyloid beta and tau. Amyloid beta units aggregate and form fibrils which are deposited outside neurons in characteristic clumps called plaques. Abnormal tau proteins also aggregate together into masses inside cells known as neurofibrillary tangles. Plaques and tangles consequently cause brain cells to become injured and die, resulting in memory loss and behavioral changes.

A lot of recent research aimed at finding ways to thwart Alzheimer’s disease progression has focused on these build ups and despite promising laboratory studies, clinical trials on novel therapeutic agents have been largely disappointing. “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,” said lead researcher Gong Chen in a news-release. “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.”

In this new study, Chen’s team discovered that the brains of deceased Alzheimer’s patients possessed abnormally high concentrations of an inhibitory neurotransmitter called GABA (gamma-aminobutyric acid). In particular, they found high GABA content within star-shaped cells called astrocytes located in a brain region called the dentate gyrus. Astrocytes are the most abundant cell type in the brain and play a variety of important roles such as neuronal support.

“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,” said Chen.

In order to find out more, the researchers used a mouse model for Alzheimer’s disease (AD). These mice have a similar disease presentation to human AD patients. They found that this abnormal level of GABA in reactive astrocytes of the dentate gyrus correlated with poor performance in learning and memory tests. Furthermore, they found that an astrocyte-specific GABA transporter called GAT3/4 was responsible for this excessive GABA release, which may serve as a novel therapeutic target. This suggestion was supported by the fact that when the researchers inhibited this particular GABA transporter in the AD model mice, their memory deficit was rescued. 

“We are very excited and encouraged by this result, because it might explain why previous clinical trials failed by targeting amyloid plaques alone,” said Chen. He explained that while targeting amyloid proteins may reduce the plaques, possible downstream events triggered by amyloid deposits, such as those discovered in this study, may not be corrected by only targeting amyloid. “Our studies suggest that reducing the excessive GABA inhibition in 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,” he added. 

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