In Alzheimer’s brains, the axonal protein tau strays into dendritic spines and stirs up trouble at synapses. Researchers have called this a mislocalization, but a paper in the April 23 Journal of Neuroscience challenges this view, suggesting that tau may also perform a physiological function at the synapse. Researchers led by Alain Buisson at INSERM-Joseph Fourier University in Grenoble, France, report that tau in wild-type neurons moves into dendritic spines in response to electrical stimulation. There, the protein interacts with the actin cytoskeleton and may actively participate in the spine remodeling that underlies synaptic plasticity, the authors suggest. By contrast, in neurons treated with Aβ, tau idles in spines, and synaptic stimulation then causes them to collapse. “Somehow, Aβ disrupts the link between activity and tau translocation, as well as the plasticity potential of synapses,” Buisson told Alzforum.
The findings are surprising, said Dezhi Liao at the University of Minnesota, Minneapolis. He was not involved in the work. “The data raise a lot of new questions. What is tau doing at the synapse? How do the normal process and the disease process interact?” Future studies should look more closely at whether synaptic tau benefits or harms the cell, and how phosphorylations affect its behavior, Liao suggested.
Previous research has established that Aβ causes the migration of tau into dendritic spines. Various studies have found that this tau can dampen synaptic signaling (see Jan 2011 news story), mediate excitotoxicity through the kinase Fyn (see Jul 2010 conference story), and abolish spines (see Sep 2010 news story). On the other hand, some recent studies have hinted at a role for the protein in normal synaptic function as well. Lack of tau contributes to spine loss in cultured neurons (see Chen et al., 2012), and tau has been found to interact with synaptic proteins such as NMDA receptors in wild-type cells (see Mondragon-Rodriguez et al., 2012).
To further investigate tau’s role at the synapse, first author Marie Lisa Frandemiche transfected primary cortical neurons from mice with fluorescently-tagged tau. Under resting conditions, tau occupied the shafts of axons and dendrites, but avoided dendritic spines. After neurons were depolarized by a pharmacological agent, the tau content of spines jumped up 50 percent (see image below). Several other synaptic proteins, including the cytoskeletal protein actin, the kinase Fyn, PSD-95, and the AMPA receptor subunit GluA1, also moved into spines. The authors saw a similar response when they induced long-term potentiation (LTP) in hippocampal slices; synaptic levels of all these proteins increased twofold.
Translocating tau: Tau (green) in the dendritic shaft avoids dendritic spines (red) until neuronal stimulation drives it in (arrowed yellow dot). [Image courtesy of, and with permission of, Frandemiche et al., The Journal of Neuroscience, 2014.]
What might tau be doing at synapses? Since tau binds and stabilizes actin filaments, the authors looked for a relationship between these two proteins. They treated cultured neurons with a compound that induces actin to polymerize, and found that tau migrated into spines just as it did after neuronal stimulation. On the other hand, treatment with a compound that breaks apart actin filaments abolished synaptic tau. The data suggest that tau responds to changes in actin, Buisson noted. As spines mature to store memories, the cytoskeleton remodels and tau may participate in this process, Buisson said.
To investigate how Alzheimer’s disease changes the picture, the authors added 100 nM synthetic Aβ oligomers to the cultures. Tau, actin, Fyn, PSD-95, and GluA1 migrated into spines just as they did after synaptic stimulation. However, subsequent neuronal stimulation suppressed synaptic levels of tau and actin, and spines shrank.
What accounts for the difference in tau’s behavior in the presence and absence of Aβ? The authors found that the protein is phosphorylated differently in the two conditions. After neuronal stimulation, residue Thr205 became phosphorylated, but after Aβ exposure, Thr205 phosphorylation dropped while Ser404 phosphorylation surged. The difference may affect tau’s ability to bind actin. When the authors blocked Thr205 phosphorylation, tau moved out of the synapse more easily, suggesting that less of it was bound to the cytoskeleton. Blocking Ser404 phosphorylation, on the other hand, prevented Aβ from driving tau to spines. In ongoing work, the authors are examining in vitro how various tau phosphorylations affect its ability to bind actin.
The data help flesh out the model of how tau mediates Aβ’s synaptotoxicity. They largely agree with previous studies, commentators said. For example, Liao and colleagues recently reported that Aβ’s ability to induce the internalization of glutamatergic receptors depends on the phosphorylation state of dendritic tau (see Miller et al., 2014). However, more research will be needed to determine what function tau performs at the synapse, commentators agreed. Hans Zempel at the German Center for Neurodegenerative Diseases (DZNE) in Bonn pointed out that the GFP-tagged tau in this study was overexpressed, leaving unclear whether endogenous tau would behave in the same way. “It is still a matter of debate whether endogenous tau plays a physiological role in dendrites and in spine plasticity,” he wrote to Alzforum (see full comment below).
Others noted that the findings support previous work linking dendritic tau to the excessive neuronal excitation induced by Aβ (see Aug 2013 news story; Dec 2013 conference story). Erik Roberson at the University of Alabama at Birmingham wrote, “Postsynaptic tau in spines may play a role in controlling susceptibility to hyperexcitation and epileptiform activity and/or in regulating long-term depression (LTD), both of which are altered in tau knockout mice.” Dendritic tau seems less likely to play a role in LTP, since tau knockouts are normal in this regard, he added (see full comment below).—Madolyn Bowman Rogers.