Jul 19, 2016

Alzheimer's Tau Protein Spreads Through the Brain Via Extracellular Space

A toxic Alzheimer’s protein can spread through the brain—jumping from one neuron to another—via the extracellular space that surrounds the brain’s neurons.

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The spread of the protein, called tau, may explain why only one area of the brain is affected in the early stages of Alzheimer’s but multiple areas are affected in later stages of the disease.

“By learning how tau spreads, we may be able to stop it from jumping from neuron to neuron,” says Dr. Duff. “This would prevent the disease from spreading to other regions of the brain, which is associated with more severe dementia.

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Tau proteins are proteins that perform the function of stabilizing microtubules. These proteins are abundant in nerve cells. When Tau proteins become defective and fail to adequately stabilize microtubules, pathologies of the nervous system can develop such as Alzheimer’s disease.



Tau protein can transfer between neurons transneuronally and trans-synaptically, which is thought to explain the progressive spread of tauopathy observed in the brain of patients with Alzheimer's disease.

Here we show that physiological tau released from donor cells can transfer to recipient cells via the medium, suggesting that at least one mechanism by which tau can transfer is via the extracellular space.

Neuronal activity has been shown to regulate tau secretion, but its effect on tau pathology is unknown.

Using optogenetic and chemogenetic approaches, we found that increased neuronal activity stimulates the release of tau in vitro and enhances tau pathology in vivo.

These data have implications for disease pathogenesis and therapeutic strategies for Alzheimer's disease and other tauopathies.

In the new study scientists discovered how tau travels by tracking the movement of tau from one neuron to another.

Tau can be released by neurons into extracellular space, where it can be picked up by other neurons. Because tau can travel long distances within the neuron before its release, it can seed other regions of the brain.
“This finding has important clinical implications,” explains Dr. Duff. “When tau is released into the extracellular space, it would be much easier to target the protein with therapeutic agents, such as antibodies, than if it had remained in the neuron.”
A second interesting feature of the study is the observation that the spread of tau accelerates when the neurons are more active.
  • Research team members showed that stimulating the activity of neurons accelerated the spread of tau through the brain of mice and led to more neurodegeneration.
Although more work is needed to examine whether those findings are relevant for people, “they suggest that clinical trials testing treatments that increase brain activity, such as deep brain stimulation, should be monitored carefully in people with neurodegenerative diseases,” Dr. Duff says.

The study was published online in Nature Neuroscience - Neuronal activity enhances tau propagation and tau pathology in vivo.

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Karen Duff, PhD, is a professor in the Department of Pathology & Cell Biology and in the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain. She is also a professor in the Department of Psychiatry at Columbia.

Jessica Wu, PhD, was a postdoctoral researcher in the Duff lab but is currently a postdoctoral researcher at Massachusetts Institute of Technology.

Abid Hussaini, PhD, is an assistant professor of pathology & cell biology (and the Taub Institute).

Gustavo Rodriguez, PhD, is a postdoctoral researcher in the Duff lab in the Taub Institute.

This work was supported by a BrightFocus Foundation fellowship, NIH/NINDS grants, Cure Alzheimer’s Fund, the Parkinson’s Disease Foundation, and the NIHR Queen Square Dementia Biomedical Research Unit.

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