In Surprise Finding, Tau Enzyme Seen in Early Alzheimer’s Stages to Protect Neurons

A process believed to trigger toxicity and neuron death in Alzheimer’s disease may actually work to protect neurons in early disease stages — a finding that may be translated into treatments that boost this protective effect.

Phosphorylated tau, which tends to aggregate into tangles inside neurons and is widely believed to mediate the toxicity of amyloid-beta in Alzheimer’s brains, actually has an initial protective effect, the researchers reported, calling it a “surprising” outcome.

The study, “Site-specific phosphorylation of tau inhibits amyloid-β toxicity in Alzheimer’s mice,” was published in the journal Science.

Most researchers today believe that neurodegeneration and memory problems in Alzheimer’s are caused by a buildup of amyloid-beta in the brain. This accumulation, in turn, causes a protein called tau to become heavily tagged with phosphor molecules and aggregate into tangles.

Working with a group of enzymes that can place the phosphor tags on tau, researchers at the University of New South Wales in Australia discovered that one of them — called p38γ kinase — was progressively lost in the brains of Alzheimer’s patients, as well as a mouse model of the disease.

The team, using mouse experiments, then set off to explore the effects of this factor. To their amazement, they discovered that it served to protect neurons from the toxicity of amyloid-beta.

When reintroducing the enzyme in mice genetically designed to lack p38γ kinase, it protected the animals from memory deficits and early death, despite having no effect on the levels of amyloid-beta.

“We used mice to screen for a very specific toxicity that we knew from previous work is involved in the progression of the disease,” Lars Ittner, a professor at UNSW and the study’s senior author, said in a news release.

“We set out to find mediators of this progression, which led us quickly to our surprising finding. It was the opposite of what we expected. It was only when we changed our view of the process involved in the development of Alzheimer’s disease that these results started to make sense.”

Further studies confirmed that the protective effect of the enzyme rested on its potential to phosphorylate tau.

“Amyloid-beta induces toxicity in the neurons, but the first step in tau phosphorylation is actually to decrease this toxicity. This is a completely new mindset; that the reason tau becomes modified is actually to protect from damage,” said Ittner, who believes that the protective effect is eventually lost.

The research team is now working to translate the findings into a treatment that could benefit patients.

“If we can stimulate that activity, we may be able to delay or even halt the progression of Alzheimer’s disease,” Ittner said.