JHU team demystifies 'one-two punch' that causes Alzheimer’s disease

In Alzheimer’s disease, the interaction between the buildup of tau proteins inside brain nerve cells and the accumulation of beta-amyloid outside these cells has been unclear. Using mouse models, Johns Hopkins scientists have shed light on this relationship, which could pave the way to more effective therapies.

Previous studies of early-onset Alzheimer’s have suggested the aggregation of beta-amyloid outside the cells is responsible for the clumping of tau proteins inside them, which causes brain cell degeneration and dementia. Instead, the new study shows that beta-amyloid buildup “is insufficient” to cause tau to “convert” from a normal state into an abnormal state in which it accumulates. Instead, it indirectly affects tau buildup by bringing about a “chain of chemical signaling events” that leads to its “conversion” into its clumping state.

“For the first time, we think we understand that the accumulation of amyloid plaque alone can damage the brain, but that’s actually not sufficient to drive the loss of nerve cells or behavioral and cognitive changes,” Wong said in a statement. “What appears to be needed is a second insult--the conversion of tau--as well.”

The team crossbred two groups of genetically modified mice to create a model that reflected more accurately the development of dementia in humans. The first group was engineered to accumulate beta-amyloid, while the second was engineered to accumulate tau protein in response to a tau fragment. They found in brain dissections that while beta-amyloid plaques weren’t able to directly “convert” tau to an abnormal state, their presence in the brain was still needed for tau to start clumping.

This could be why some drugs intended to treat Alzheimer’s after the “conversion” of tau have failed, Wong said in the statement. “If you were to intervene in the time period before the conversion of tau, you might have a good chance of ameliorating the deficits, brain cell loss and ensuing consequence of the disease,” he said. And the results also suggest that a combination therapy to combat the buildup of beta-amyloid and the clumping of tau could be successful.

- here's the statement

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