Amyloid-β plaques accumulating in the brain alone are not enough to cause the dementia that characterizes Alzheimer’s, new research from Johns Hopkins University argues. Instead, a second blow — molecular pathways that ultimately cause tau proteins to form tangles inside nerve cells — is also needed for neurons to degenerate.
The study, “The neuritic plaque facilitates pathological conversion of tau in an Alzheimer’s disease mouse model,” published on Monday in the journal Nature Communications, might debunk the notion that amyloid-β plaques are disease-causing in their own right.
“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,” said Philip C. Wong, a professor of pathology at the university’s School of Medicine, in a press release. “What appears to be needed is a second insult — the conversion of tau — as well.”
The two processes — aggregation of amyloid-β into clumps outside brain cells, and the formation of so-called fibrillary tangles by tau protein inside cells — have both been well investigated in Alzheimer’s disease.
Tau proteins are necessary components of healthy brain nerve cells, but in Alzheimer’s, unknown factors increase the labels — in the form of phosphate molecules — normally controlling their function. This process, called hyperphosphorylation, makes the proteins stick to each other and form tangles.
Amyloid-β protein aggregation in tissue makes the brains of Alzheimer’s patients look so obviously different from those of healthy people that many researchers have concluded plaques are somehow causing Alzheimer’s. The question whether amyloid-β in itself is both enough and necessary to start disease processes has, however, is still debated.
A generally accepted theory is that amyloid-β aggregates — known to occur early on in humans who later develop Alzheimer’s — trigger the formation of tau fibrils inside nerve cells, directly causing dementia, but the relationship and timing between the two processes are far from clear.
Researchers used a new genetically engineered mouse model to show that the accumulation of amyloid-β is not enough to trigger the formation of tau tangles. Instead, it spurs a chain of events involving various signaling molecules that turns on the hyperphosphorylation and aggregation of tau.
The discovery was made possible with the help of a new mouse model. Previous models using mice producing human amyloid-β in their brains have not been able to capture the crucial factor of timing.
While in humans, amyloid plaques can be detected at least 10 years before tau starts misbehaving, mice live for two or three years — far too short to track the details of the relationship.
To overcome this constraint, researchers cross-bred a mouse accumulating amyloid-β with one genetically altered to accumulate tau upon the introduction of a tau fragment. Analyzing the brains of these mice, researchers discovered that neither the presence of amyloid-β nor triggering tau accumulation, alone, was enough to cause disease. Instead, both factors needed to be present.
The study’s findings might explain why drugs attempting to reverse the disease by targeting amyloid plaque have not worked. “The timing may be off,” said Wong. “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.”
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