The Role of Astrocytic Tau Deposition onto Synaptic and Memory Dysfunction

Background In Alzheimer's and other brain diseases, tau protein can become misshapen and form disease-related clumps in the brain. One such clump, known as an 'oligomer,' contains only a few tau molecules and often develops early on in disease. Tau oligomers can form in 'support' cells called astrocytes, which normally support, among other things, the function of synapses (specialized structures through which nerve cells communicate with each other). But when tau oligomers develop in astrocytes, they hinder these support functions by reducing levels of a protein called glutamate-transporter-1 (GLT-1). Astrocytes need GLT-1 to remove excess glutamate (a chemical messenger) in the brain, and loss of GLT-1 may lead to abnormal glutamate concentration around synapses, which, in turn, may cause synapse damage. Ultimately, this damage can lead to memory loss and dementia. In initial research, Dr. Eleni-Kostantina Argyrousi and colleagues analyzed brain samples from mice with high levels of astrocytic tau. They found that the samples showed damage to synaptic function. They also observed that this function could be restored with a compound called Tanespimycin, which boosts GLT-1 production by reducing a protein which lowers GLT-1 levels called heat shock protein 90-beta (Hsp90β). Such findings indicate the need to better understand how astrocytic tau, GLT-1 and synaptic dysfunction are linked in brain disease. Research Plan Dr. Argyrousi and colleagues will now conduct a larger study to expand on their earlier work by first collecting brain samples from mice that have been treated with compounds that can increase the levels of tau oligomers in astrocytes. They will then determine how synaptic structure and function are impacted by astrocytic tau oligomers in the brain samples. Next, they will determine how tau oligomers affect the distribution of GLT-1 and Hsp90β in both astrocytes and nerve cells, and how GLT-1 and Hsp90β interact in different brain regions. The investigators will then treat another group of mice with compounds to boost astrocytic tau, and then subsequently treat them with Tanespimycin to increase levels of GLT-1. They will administer various memory tests to the mice to understand how Tanespimycin treatment may have prevented tau-related memory loss. Lastly, the researchers will determine how Tanespimycin impacted synaptic structure and function. Impact The results of this project could shed new light on how brain cell communication and memory loss develop in brain disease. They could also identify GLT-1 as a target for novel memory therapies.