Toxic tau protein, untangled but donning a pair of acetyl groups, infiltrates synapses and prevents memory formation, according to a paper in the March 31 Neuron online. The study explains one way tau can interfere with cognition, say the researchers, led by senior author Li Gan at the Gladstone Institute of Neurological Disease in San Francisco. They traced weakening of neural plasticity to a crucial synaptic protein known as KIBRA, which disappears when acetylated tau arrives in the synapse. The authors claim KIBRA is the “missing link” between tau and memory loss.
“This is a really phenomenal paper,” commented Todd Cohen of the University of North Carolina in Chapel Hill, who was not involved in the study. “We have to consider acetylation as a dominant player in controlling tau function at the synapse, and possibly elsewhere.”
Hyperphosphorylated tau has long been known to accumulate and aggregate in the brains of people with Alzheimer’s or frontotemporal dementia. Over the last few years, however, a handful of scientists have turned their attention to a different tau modification—acetylation. The acetyltransferase p300 attaches acetyl groups to lysine residues in tau. Upward of 20 tau lysines may be subject to such modification, though Gan said the precise number is uncertain. Both histone deacetylase 6, SIRT1, and potentially other deacetylases can remove the groups. In 2010, Gan and colleagues reported that acetylation protects tau from degradation, allowing hyperphosphorylated tau to accumulate (see Sep 2010 news on Min et al., 2010).
To identify acetylation sites relevant to disease, the authors used mass spectrometry to analyze tau from the brains of people who died of Alzheimer’s. They found acetyl groups at lysines 174, 274, and 281. In 2015, the Gan lab reported that a version of tau with a glutamine in place of lysine-174, which mimicked the acetylated tau, caused hippocampal atrophy and memory defects in mice (see Sep 2015 news). In the new paper in Neuron, first author Tara Tracy and colleagues focused on the other two sites, which occur in the protein’s microtubule-binding domain.
Tracy generated transgenic mice (tauKQ) that expressed human tau with glutamine residues at positions 274 and 281. Another line, called tauKQ-high, expressed about 20 percent more of this construct. The tauKQs got phosphorylated, but did not form tangles.
Both tauKQ mice acted fairly normally, and lived full lifespans. However, in a water maze, tauKQ-high mice failed to recall the location of a hidden platform, indicating they had difficulty with spatial memory. Tracy also assessed whether the tauKQ-high mice failed to form or distinguish two similar memories, as people with mild cognitive impairment or AD are thought to do (Ally et al., 2013; Wesnes et al., 2014; Yassa et al., 2010). She tested memory in a fear-conditioning experiment that utilized two very similar contexts (Nakashiba et al., 2012; McHugh et al., 2007). She trained the mice in two identical cages that had different environmental cues. One smelled like Windex and had background noise from a fan. The other smelled like Simple Green and contained a solid black, tent-like cover inside. Only in the noisy Windex cage did the mice receive a foot shock. After a learning period, nontransgenic mice came to recognize that the Simple Green cage was safe, and were less likely to freeze in anticipation of a shock when placed in it. In contrast, TauKQ-high mice froze in both cages, indicating they had trouble differentiating the two.
Tracy found a potential explanation for these memory deficits when she measured long-term potentiation, which is needed for synaptic remodeling, in hippocampal slices. When she stimulated neurons in the dentate gyrus—the part of the hippocampus responsible for distinguishing memories of similar objects or environments—their output stayed high for more than an hour in slices from nontransgenic mice and mice expressing wild-type human tau. In the tauKQ lines, the output dropped faster, indicating the synapse was unable to maintain strength.
The authors suspected this defect resulted from failure to deliver AMPA receptors to the spine tips, as normal dendrites do. Tracy tested this in hippocampal rat neurons expressing tauKQ or wild-type tau. On applying glycine to stimulate long-term potentiation, the tauWT neurons polymerized actin, which is needed for receptor transport, and dispatched AMPA receptors to the spine surfaces. The tauKQ neurons did neither. Going back to the mouse hippocampal slices, Tracy treated them with jasplakinolide, which polymerizes actin. This restored the long-term potentiation of tauKQ-high slices to normal, suggesting acetylated tau acts upstream of actin polymerization to disrupt synaptic plasticity.
Next, Tracy and Gan wondered what molecule might link tau to actin polymerization. They considered the kidney/brain postsynaptic protein, KIBRA. It interacts with AMPA receptors and proteins that regulate actin (Duning et al., 2008; Kremerskothen et al., 2003; Kremerskothen et al., 2005). In genetic studies, KIBRA has been linked to memory performance in cognitively healthy people (see Oct 2006 news) as well as late-onset Alzheimer’s (Rodríguez-Rodríguez et al., 2009; Corneveaux et al., 2010; Burgess et al., 2011). Mice lacking KIBRA have impaired long-term potentiation and memory (see Oct 2011 news). Tracy and Gan discovered less KIBRA in brain homogenates from people who died of AD, compared with non-demented control brains.
To test whether KIBRA participated in the synaptic plasticity pathway that tau interfered with, Tracy returned to the cultured neurons expressing tauKQ. Co-expressing excess KIBRA restored their ability to polymerize actin and traffic AMPA receptors. While they have not yet worked out how, the authors present a model whereby acetylated tau causes a drop in KIBRA at the synapse. Their experiments indicate that the loss of KIBRA leads to poor actin polymerization and AMPA receptor transport, and impaired synaptic plasticity (see image above).
This is just one of many ways tau could be toxic, noted scientists who spoke with Alzforum. “I would not be surprised if there are other actions of acetylated tau,” commented Li-Huei Tsai of the Massachusetts Institute of Technology, who did not participate in the work. She wondered if acetylation might also affect toxic actions such as the seeding of tau aggregates or its spread between cells. The combination of acetylation, phosphorylation, and aggregation likely works in concert to make tau dangerous, Tsai said. In fact, Cohen’s work suggests one such interaction; acetylation promotes tau fibril formation, at least in vitro (see Mar 2011 news).
Cohen noted that tau can be phosphorylated at 40-some sites, acetylated at another couple of dozen, and is subject to other modifications such as glycosylation and methylation too (see Jul 2015 news; Song et al., 2015). “We may have a very complex code of modifications,” he said. Studying how those different modifications work together—rather than just as one or two at a time, as Tracy did—will be important in future research, he said. While this will be complicated to do, he suggested computational or proteomics methods might help crack the code.
In the meantime, Gan and colleagues are already hoping to apply what they have learned about tau acetylation for therapeutics. The anti-inflammatory medication salsalate inhibits p300, the tau acetyltransferase, and Gan and Adam Boxer at the University of California in San Francisco are already testing it in people with the tauopathy progressive supranuclear palsy. Gan said she is interested in trying salsalate in people with Alzheimer’s, too, even as she works to identify compounds that would more potently and specifically inhibit p300. The new work suggests that if scientists could find small molecules that enhance KIBRA function, they too might have clinical potential. Tsai pointed out enhancing SIRT1’s ability to remove acetyl groups might also be beneficial.—Amber Dance
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