Alzheimer’s May Progress Through Spread of a Brain Tau Protein

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Alzheimer's disease study

Scientists at Massachusetts General Hospital (MGH) have published a new study describing how neurofibrillary tangles — one of the hallmarks of Alzheimer’s disease — develop.

Alzheimer’s disease is characterized by a progressive degeneration of specific brain regions, starting with those areas involved in memory. Two proteins are found at high levels in the brains of people with Alzheimer’s, beta-amyloid and hyperphosphorylated tau. Scientists have long debated whether or not these proteins are a cause or consequence of Alzheimer’s disease. But more recently, researchers have agreed that tau indeed seems to be a key player underlying the brain cell death found in Alzheimer’s disease.

In the report, titled Neuronal uptake and propagation of a rare phosphorylated high-molecular-weight tau derived from Alzheimer’s disease brain and published in the journal Nature Communications, researchers described how phosphorylated tau, the protein responsible for neurofibrillary tangles, spreads through the brains of people with Alzheimer’s disease.

“It has been postulated that tangles — the abnormal accumulation of tau protein that fills neurons in Alzheimer’s disease — can travel from neuron to neuron as the disease progresses, spreading dysfunction through the brain as the disease progresses. But how that happens has been uncertain,” remarked Bradley Hyman, MD, PhD, director of the Massachusetts General Hospital Alzheimer’s Disease Research Center and a study author. “Our current study suggests one mechanism at play is that a unique and rare type of tau has the properties we were looking for — it is released from neurons, taken up by other neurons, transported up and down axons, and then released again.”

Tau first appears in brain regions called the entorhinal cortex and hippocampus, structures that are known to be responsible for processing memory. It then spreads to other brain regions, causing increased damage and debilitating symptoms. However, it is not understood how tau might spread from neuron to neuron.

The team took tau protein from the brains of genetically altered mice, known as tau transgenic mice, that have an experimental form of Alzheimer’s disease and produce an excessive amount of tau protein in their brains, similar to what is observed in Alzheimer’s disease. The results showed that only 1 percent of all tau found in neurons grown in a dish was actually taken up by those neurons. The specific type of tau seemed to be of a higher molecular weight, in other words, it contained more protein linked together.

“Our findings suggest that the release and uptake of this form of tau is an important step in the spread of disease from one brain region to another,” said Dr. Hyman, a John Penny Professor of Neurology at Harvard Medical School. “Since that spread likely underlies clinical progression of symptoms, targeting the mechanisms of the spreading might hold promise to stabilize disease,” and possibly form the basis for future treatments in Alzheimer’s disease.