Animal studies suggest that innate immune system cells may help mutant tau protein spread through the brains of patients with neurodegenerative disease.

Tau-containing vesicles secreted by microglia appear to be instrumental for propagating tau tangles between different brain areas.

Those vesicles, which are called exosomes, could be therapeutic targets for halting the spread of tangles in neurodegenerative disorders.

Tau tangles, along with amyloid plaques, are the major protein aggregates in Alzheimer’s disease (AD). And tangles correlate better with cognitive dysfunction than plaques do, providing a rationale for their therapeutic targeting. (See BioWorld Insight, July 2, 2015.)

Tau also aggregates in other neurodegenerative disorders – both those that occur in aging, such as frontotemporal dementia, and some metabolic disorders. Collectively, those diseases go by the moniker “tauopathies.”

Tau protein binds to microtubules, which make up the highway along which motor proteins transport cellular cargo. When tau cannot bind, intracellular transport is disrupted.

Although noticeable tau pathology appears later in the course of AD than amyloid plaques, they are like plaques in that by the time cognitive dysfunction is evident, tangle formation has been going on for years.

“There is an accumulation of tau protein . . . prior to the development of Alzheimer’s disease,” Tsuneya Ikezu told BioWorld Today.

Ikezu is a professor of pharmacology and experimental therapeutics and neurology at Boston University School of Medicine, and the senior author of the report describing the findings, which he and his colleagues published in the Oct. 5, 2015, issue of Nature Neuroscience.

Furthermore, the development of tau tangles begins in specific hot spots of the brain and propagates out from there.

But it propagates slowly – which is good news in the clinic, but bad news for researchers trying to understand how it propagates. So Ikezu and his team “wanted to speed up propagation,” he explained.

They did so by delivering high amounts of tau protein to one part of the hippocampus, a brain structure involved in memory formation that is damaged in Alzheimer’s disease. After such delivery, they could see tau spreading to other parts of the hippocampus within months, rather than the years the process normally takes.

They then demonstrated that microglia, innate immune system cells that conduct immunosurveillance in the brain, were important for the spread of tau.

Microglia normally take up debris from the environment, digest it and secrete it via exosomes as a way to present antigens to other immune system cells.

When neurons are damaged in neurodegenerative diseases, “microglia engulf the sick neurons and try to phagocytose them,” he said.

In AD and other neurodegenerative disorders, though, a lot of tau protein is misfolded and very difficult to digest.

“Usually microglia secrete undigested molecules to keep the cell healthy,” Ikezu explained. But “under disease conditions, they end up secreting the pathogenic molecule.”

From a scientific perspective, “one of the key findings [of the paper] is the involvement of the microglia” in spreading tau.

That finding also suggests that, like cancer, the fact that risk goes up sharply with age could to some extent be because the immune system can no longer stay ahead of longer-running problems with other systems.

“When the brain ages, perhaps the microglial metabolic function declines,” he said, leading to the spread of undigested tau to the point where clinical symptoms occur.

On a practical level, the results suggest that either microglia themselves or the exosomes they secrete could be a therapeutic target in AD and other tauopathies.

One such drug already in multiple clinical trials, both alone and in combination, is the experimental cancer drug pexidartinib (PLX3397, Plexxikon Inc.), which specifically depletes microglia.

In two separate animal models of tauopathy, animals treated with pexidartinib showed reduced tau transmission.

The team also inhibited the production of exosomes, either with short interfering RNA or through pharmacological inhibition of an enzyme that is important for the production of sphingomyelin, a major component of the microglial exosome membrane. Blocking sphingomyelin also reduced the spread of tau, without directly affecting tau’s production.