Hyperphosphorylation causes tau to form toxic aggregates that underlie a range of tauopathies, including Alzheimer’s. So goes the conventional wisdom in Alzheimer’s disease research. But could some tau phosphorylation be protective? In the November 18 Science, researchers led by Lars Ittner, University of New South Wales, Sydney, claim that by phosphorylating tau at threonine 205, mitogen-activated protein kinase p38γ prevents formation of a postsynaptic complex that mediates Aβ-induced excitotoxicity. In cell and mouse models, boosting p38γ levels protected against Aβ and seizures, while knocking out the enzyme left neurons vulnerable.
“This is an interesting study that suggests the field may have to change the way they think about tau phosphorylation in Alzheimer's disease,” said Joe Lewcock from Denali Therapeutics, South San Francisco. “It is a nice addition to our understanding of tau function and will surely provide a starting point for a range of future work.”
Ittner’s group previously reported that tau plays a crucial role in Aβ excitotoxicity (Jul 2010 news on Ittner et al., 2010). Tau targets Fyn kinase to the synapse, where the enzyme phosphorylates a subunit of the NMDA receptor. This strengthens the interaction between NMDA and PSD-95, making the synapse hyperactive. Ittner wondered if the neuron had a way to regulate this process to prevent Aβ toxicity. Ittner’s brother, first author Arne Ittner, a molecular biologist who joined the lab in 2010, had worked extensively on p38 kinases. Since p38—specifically the γ isoform—is known to interact with PSD-95, he suggested they test if the p38 kinases regulate the process. Certain p38 isoforms—β, γ, and δ, but not α—can hyperphosphorylate tau (Goedert et al., 1997).
To see how the individual isoforms of p38 contribute to the hyperexcitability caused by Aβ, the Ittners knocked out each one individually in wild-type mice, then induced seizures with the GABA(A) receptor antagonist pentylenetetrazole (PTZ). Deleting only the p38γ isoform hastened and intensified seizures. If the researchers knocked out p38γ in APP23 mice, which overexpress human APP with the Swedish mutation, the animals became more sensitive to these electrical imbalances in the brain. These mice also died younger, developed earlier and worse memory problems, and had more disrupted brain network activity than APP23 mice with active p38γ. The authors did not cross APP23 mice with any of the other p38 knockouts.
This p38γ effect seemed to depend on tau. Knocking out tau in APP23 mice did away with any ill effects of expunging p38γ. At the same time, elevated tau expression in p38γ knockouts brought on more seizures. All signs pointed to a mechanism whereby p38γ dampened tau’s ability to mediate Aβ toxicity. Interestingly, APP23 mice, APPNL-G-F knock-in mice, and postmortem tissue from AD patients all had lower levels of the enzyme compared to their respective controls.
In keeping with the idea that p38γ might regulate PSD-95/tau/Fyn complexes, the researchers found that the kinase concentrated in dendritic spines in primary hippocampal neurons (see image above). They found that raising the level of p38γ in human embryonic kidney cells reduced levels of PSD-95/tau/Fyn. Expressing a constitutively active form of p38γ, p38γCA, in the brain of APP23 mice diminished the complexes there, as well. In addition, constitutively active p38γ protected cultured neurons from Aβ toxicity and suppressed PTZ-induced seizures in wild-type mice. This constitutively active kinase restored coordinated electrical activity that is compromised in APP23 animals, and improved their performance in the Morris water maze (see image below).
How does p38γ modify tau? Based on experiments carried out in both test tubes and mice, p38γ phosphorylates tau at threonine 205 (T205). If the researchers mimicked this phosphorylation by replacing that threonine with negatively charged glutamic acid, tau interacted less with PSD-95, but its relationship with Fyn was unaffected.
Taken together, the results suggest that phosphorylating tau at T205 protects against Aβ-induced excitotoxicity, countering the idea that all tau phosphorylation is damaging. “This is the first example of a specific tau phosphorylation that has beneficial effects in the context of Aβ toxicity,” said Lars Ittner. “It challenges the dogma that all tau phosphorylation causes neuronal toxicity.” He suggested T205 might be one of many functional tau phosphorylation sites and speculated that tau phosphorylation at T205 prevents Aβ toxicity early in Alzheimer’s disease process, but that this protection becomes overwhelmed by later hyperphosphorylation. “We should rethink tau modification and examine in detail how phosphorylation at specific sites affects physiological function and disease,” Ittner told Alzforum.
Could this discovery have therapeutic implications? Possibly, said Ittner. Perhaps a drug could be developed to enhance this type of phosphorylation, he proposed. Lewcock thought this would be difficult. “From a therapeutic perspective, a wealth of data is presented supporting p38γ as the key kinase regulating tau T205 phosphorylation, though unfortunately the development of compounds that act as kinase activators has proven far less tractable than [developing] kinase inhibitors,” he said.
Ittner also advised caution about developing p38 inhibitors or other drugs that might inadvertently block p38γ. “I would be concerned about inhibiting p38 generally,” he said. “I would strongly urge people to look for specific inhibitors that do not inhibit the γ form of p38,” said Ittner. One p38 inhibitor called VX-745 has been tested in Phase 2 trials of people with mild cognitive impairment due to AD or mild AD (Dec 2014 conference news).
Researchers are also developing selective p38α MAPK inhibitors for AD and other neurodegenerative diseases (Roy et al., 2015). In microglia, this isoform regulates the release of pro-inflammatory cytokines in response to stressors such as Aβ42.—Gwyneth Dickey Zakaib
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Research Models Citations
- Ittner LM, Ke YD, Delerue F, Bi M, Gladbach A, van Eersel J, Wölfing H, Chieng BC, Christie MJ, Napier IA, Eckert A, Staufenbiel M, Hardeman E, Götz J. Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer's disease mouse models. Cell. 2010 Aug 6;142(3):387-97. Epub 2010 Jul 22 PubMed.
- Goedert M, Hasegawa M, Jakes R, Lawler S, Cuenda A, Cohen P. Phosphorylation of microtubule-associated protein tau by stress-activated protein kinases. FEBS Lett. 1997 Jun 2;409(1):57-62. PubMed.
- Roy SM, Grum-Tokars VL, Schavocky JP, Saeed F, Staniszewski A, Teich AF, Arancio O, Bachstetter AD, Webster SJ, Van Eldik LJ, Minasov G, Anderson WF, Pelletier JC, Watterson DM. Targeting human central nervous system protein kinases: An isoform selective p38αMAPK inhibitor that attenuates disease progression in Alzheimer's disease mouse models. ACS Chem Neurosci. 2015 Apr 15;6(4):666-80. Epub 2015 Feb 23 PubMed.
- New Target for Tauopathies? Blocking Nuak1 Could Reduce Tau Build-Up
- Tipping the Balance Toward Four-Repeat Tau Exacerbates Toxicity in Mice
- Stress Granule Protein Entwines and Misfolds Tau
- ROCK’n the Tau Pathway?
- Inventory of Tau Modifications Hints at Undiscovered Functions
- Could Kink in Tau Lead to Neurodegeneration?
- Ittner A, Chua SW, Bertz J, Volkerling A, van der Hoven J, Gladbach A, Przybyla M, BI m m, van Hummel A, Stevens CH, Ippati S, Suh LS, Macmillan A, Sutherland G, Kril JJ, Silva AP, Mackay J, Poljak A, Delerue F, Ke YD, Ittner LM. Site-specific phosphorylation of tau inhibits amyloid-b toxicity in Alzheimer’s mice. Science. 2016 Nov 18; 354(6314):904-8.