How neurons fend off Alzheimer’s with a cellular broom that clears the toxic tau protein

When the protein tau builds up inside the neurons of the brain, the cells become impaired and eventually die in a process that’s been implicated in Alzheimer’s and other neurodegenerative diseases. But some neurons never get clogged up with tau—and a team of scientists led by the Columbia University Vagelos College of Physicians has discovered why.

Neurons naturally undergo a cellular "cleaning system" that relies on several proteins, including one called BAG3, according to a statement from Columbia. That system clears tau from neurons and protects against Alzheimer’s. But in some neurons, the cellular broom is sluggish. Manipulating BAG3 could offer a way to revive its ability to sweep tau out of the cells, the researchers reported in the journal Nature Neuroscience.

The team made the discovery by using new technologies that allowed them to watch individual brain cells in action, they reported. Working with mouse neurons, they changed the levels of BAG3 inside the cells then observed their responses. When they amped up BAG3, the neurons cleared excess tau, they discovered. But when they lowered BAG3 levels, the toxic protein was able to cripple the cells.

"If we can develop therapies to support these natural defense mechanisms and stop tau from accumulating, we might be able to prevent, or at least slow, the development of Alzheimer's and other tau-related neurodegenerative diseases," said lead author Karen Duff, Ph.D., professor of pathology and cell biology at Columbia, in the statement.

Any new approach to combating tau will most certainly be of interest to the Alzheimer’s research community, which has so far struggled to come up with therapies that are effective against the disease. Earlier this month, scientists at the University of California, Los Angeles, boosted the genetic understand of tau by describing how mutations in two gene clusters cause an overproduction of the protein.

In September, Massachusetts General Hospital and Johns Hopkins researchers showed how tau disrupts the exchange of proteins and RNA in the brain, causing a further buildup of the toxic protein.

And one recent deal proves that there’s still an intense interest in anti-tau approaches to Alzheimer’s. Last week, Eli Lilly laid out $81 million to license AC Immune’s tau-fighting drug ACI-3024. In preclinical studies, AC Immune showed that the drug inhibits tau aggregation, but the company still has a long way to go to prove that this slows down memory loss.

The Columbia team discovered in its research that harmful tau accumulates primarily in a subset of brain cells called excitatory neurons, which other researchers had previously noted are particularly vulnerable to degeneration in Alzheimer's disease. "We anticipate that further demonstrations of the complex and highly regulated interactions between different protein homeostasis components will reveal more determinants of the vulnerability of specific neuron types," they wrote in their study.

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