Researchers identify potential drug target for frontotemporal dementia

Frontotemporal dementia is estimated to account for around 10-15% of all dementia cases in the USA, with the majority of patients only surviving an average of 6-8 years after diagnosis. 

However, in a new study, researchers from the University of Alabama at Birmingham say they may have uncovered a potential drug target for the disease.

Researchers found that mutated tau impairs the connections between neurons by reducing the size of anchoring sites for NMDA (N-methyl-D-aspartate) receptors crucial for brain signaling.

Frontotemporal dementia (FTD) is characterized by rapid deterioration of language skills, movement and changes in personality, behavior and social skills. 

Onset of FTD most commonly occurs during mid-late 50s - significantly earlier than the average age of Alzheimer's disease onset.

FTD is believed to be triggered by cell degeneration in the frontal or temporal lobes of the brain. 

Although it is unclear exactly what causes this cell degeneration, past studies have indicated that it may be caused by mutations in genes that express a protein called tau; an accumulation of tau has also been associated with Alzheimer's.

But the researchers of this latest study at the Department of Neurology of the University of Alabama at Birmingham - note that little is known about how tau mutations affect certain brain regions, leading to FTD.

NMDA receptor identified as drug target for FTD

To find out more, the research team analyzed novel mouse models that possessed a mutated human tau gene and displayed behaviors similar to those found in humans with FTD.

Results of the analysis - published in The Journal of Neuroscience - revealed that the mutant tau present in the mouse models interfered with connections between neurons - called synapses - by decreasing the size of anchoring sites for NMDA (N-methyl-D-aspartate) receptors crucial for brain signaling.

Reduction of the anchoring sites left fewer NMDA receptors available at the synapse to receive excitatory signals, thus limiting synaptic firing and network activity.

Next, the team tested the effects of an existing drug approved by the Food and Drug Administration (FDA) - cycloserine - in the mouse models. 

Cycloserine - an antibiotic usually prescribed for tuberculosis - is known to boost the function of NMDA receptors.

The researchers found that cycloserine was able to increase NMDA receptor function in the mouse models, which restored synaptic signaling and reversed FTD-related behaviors.

Commenting on the team's findings:

"This study provides mechanistic insight into how a tau mutation affects specific brain regions to impair a network. It also provides a potential therapeutic target, the NMDA receptor, which appears to correct the network and behavioral abnormalities."

The researchers say their findings indicate that boosting NMDA receptor function could potentially treat humans with FTD.

In addition, although their findings need to be confirmed with further animal studies, the team says cycloserine could be used to boost NMDA receptor function in human trials.

Another team of researchers recently reported on a study by researchers from Washington University, suggesting that targeting a sleep-wake protein called orexin could prevent Alzheimer's.

References:

1. Tau-mediated NMDA receptor impairment underlies dysfunction of a selectively vulnerable network in a mouse model of frontotemporal dementia, Erik Roberson, et al., The Journal of Neuroscience, doi: 10.1523/JNEUROSCI.3418-14.2014, published online 3 December 2014, abstract.
2. University of Alabama at Birmingham news release, accessed 5 December 2014.
3. Additional source: Alzheimer's Association, frontotemporal dementia, accessed 5 December 2014.