NEW YORK (GenomeWeb) – Researchers at Australia's University of New South Wales have identified a form of phosphorylated tau that appears to protect against Alzheimer's disease.
The findings, reported in a study published today in Science, run counter to the traditional understanding of phosphorylated tau's role in Alzheimer's, which generally holds that the modified protein helps drive the disease process. Identification of an apparently protective form of phosphorylated tau doesn't suggest this conventional view is incorrect, said Lars Ittner, a professor at UNSW and senior author on the study, but, he noted, it suggests that tau phosphorylation may play roles in normal brain physiology that have received little attention to date.
"The physiological function of tau is generally very understudied," Ittner told GenomeWeb. "I would say that no one has really looked before at the positive effects of tau phosphorylation in Alzheimer's disease, including ourselves."
Largely, he suggested, this is due to the fact that Alzheimer's researchers first became interested in tau after discovering that tangles of tau protein appeared linked to the disease. In these tangles, tau was present in hyper-phosphorylated form, "and then the research moved backwards from there," Ittner said.
"So it is a longstanding dogma that tau is hyper-phosphorylated [in Alzheimer's patients] and that causes neuronal dysfunction," he said. Phosphorylated tau, along with total tau and amyloid-beta, is one of the most well-established protein biomarkers for diagnosing the disease.
The UNSW team's discovery of the apparently protective effects of certain phosphorylated tau forms complicates this understanding, however.
The researchers identified this protective effect through their work on the neuronal p38 mitogen-activated protein kinase p38γ and its role in Alzheimer's. As they noted in the Science paper, a common model of Alzheimer's holds that tau and Aβ interact to cause neuronal dysfunction, with tau phosphorylation thought to be a key part of the process that leads to deposition of the Aβ plaques and tau tangles that are characteristic of the disease.
Among the molecules identified as being linked to this process are p38 kinases. To better establish their role, Ittner and his colleagues examined a number of Alzheimer's mouse models containing deletions of various p38 kinases.
Looking at mice with individual knockouts for p38α, p38β, p38γ, and p38δ, they found that the p38γ knockouts showed an increase in the seizures characteristic of that mouse model for the disease while knockouts of the other kinases had no effect. They also found that treatment with a pan-p38 inhibitor also increased seizures, much like in the p38γ knockouts.
Investigating the effects of p38γ deletion further, the researchers found that loss of the kinase was associated with a variety of negative effects in their Alzheimer's mouse model, including increased excitotoxicity, neuronal circuit synchronicity, memory deficits, and mortality. They also found that humans with Alzheimer's had lower levels of the kinase.
Looking at Alzheimer's mice models both with and without tau knocked out, the UNSW researchers found that the mice without tau did not suffer from neuronal network dysfunction or any reduction in survival or memory upon deletion of p38γ, indicating that the kinase's protective effects were tau related.
Following up this finding with in vitro kinase assays along with antibody-based and mass spec analyses, the researchers identified 18 phosphosites on tau that were phosphorylated by p38γ, and, additional assays found that phosphorylation of the tau T205 residue in particular disrupted the SD-95/tau/Fyn complexes that Ittner and his colleagues had previously identified as mediating Aβ-induced excitotoxicity.
That, Ittner said, indicates that the protective effects they observed are due to phosphorylation of the T205 phosphosite.
"I think for p38γ we have pretty thoroughly nailed that down," he said. "There are other sites that are phosphorylated [by p38γ] at very low abundances, but it is that T205 site that is really the key."
Since this initial work, he and his colleagues have begun looking at additional kinases "and the connection of other [tau] phosphorylation sites to one another and to biological function," Ittner said. In addition to their mouse model work, the researchers have also established a relationship with a brain banking group in Australia that will provide them access to human samples, he said.
"We've been really prompted by our study to understand the complexity of tau phosphorylation and how and when it happens in detail to maybe find more about tau that can be potentially exploited for future therapies," said Arne Ittner, Lars' brother and a post-doc at UNSW and first author on the Science paper.
Lars Ittner noted that there are around 85 potential phosphorylation sites on tau proteins and a number of different kinases known to contribute to hyper-phosphorylation of the protein. However, he said that he is currently most interested in investigating the mechanisms of tau phosphorylation in normal physiology.
"What contributes to physiological phosphorylation [of tau] and in what compartments of the cell and under what circumstances — that is what we are trying to understand next," he said.
One party that has looked deeply at tau phosphorylation as it relates to Alzheimer's is UK-based proteomics firms Proteome Sciences. Company researchers and their collaborators recently published a paper in the Journal of Alzheimer's Disease in which they identified 47 different tau phosphopeptides covering 31 different phosphorylation sites and 11 tau phosphopeptides that were upregulated by 40 percent or more in Alzheimer's patients compared to controls.
Speaking to GenomeWeb this week about the UNSW study, Ian Pike, Proteome Sciences' chief operating officer, called the work "really very impressive" and said that the Science paper's finding that phosphorylation at the T205 phosphosite had an apparently protective effect was "fundamentally intriguing and suggests that tau plays a complex series of roles in the evolution of brain pathology in Alzheimer's disease."
Pike offered one note of caution, observing that phosphorylayed T205 has been detected in the hyper-phosphorylated tau tangles found in the brains of Alzheimer's patients. He noted, as well, that the Science study found that p38γ also increased phosphorylation of the serine 199 residue, which has been linked to tau pathologies.
"Further work will be necessary to contextualise individual phosphorylation site effects in multiply phosphorylated tau," he said.