Scientists identified a sequence of events involving immune cells and proteins that become abnormal in Alzheimer's disease. They suggest that this could be the starting point for the brain-wasting disorder and they identify two proteins that might serve as drug targets for stopping or even reversing its symptoms.
Alzheimer's disease is a progressive disease that attacks the brain. It is the most common cause of dementia, which is a condition that gradually diminishes people's ability to remember, think, carry on a conversation, and lead an independent life.
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Alzheimer's disease is the sixth leading cause of death in the United States. It is the only cause of death in the top 10 leading causes that cannot be cured, prevented, or even slowed down.
Because of the increasing number of older people in the U.S., the rate of Alzheimer's disease is growing fast. Today, an estimated 5.5 million people in the U.S. have the disease. This number could rise to 16 million by 2050.
Immune cells, amyloid, and tau proteins
The brains of people with Alzheimer's disease contain high numbers of activated immune cells together with abnormal deposits of two proteins called amyloid beta and tau. However, exactly how these factors come together to trigger and drive the disease has been somewhat of a mystery.
In the journal Cell Reports, researchers from the University of North Carolina (UNC) at Chapel Hill describe how amyloid beta triggers immune cells to cause inflammation that damages neurons, and how that damage leads to bead-like formations filled with abnormal tau.
Study leader Todd Cohen, Ph.D., an assistant professor of neurology at UNC, says, "It's exciting that we were able to observe tau - the major Alzheimer's protein - inside these beaded structures."
He says that stopping the beaded structures from forming could be a way to give people "healthier neurons that are more resistant to Alzheimer's."
The team also identified two proteins - MMP-9 and HDAC6 - that appear to promote the sequence of events that leads to bead formation. They suggest that targeting the proteins could be a way to slow or even prevent Alzheimer's disease.
The researchers began the investigation by exposing immune cells to a form of amyloid beta called oligomers, a molecular complex made from tiny clusters of the protein. This form of amyloid beta is thought to be the one that causes the most harm to brain cells.
When they examined the fluid surrounding the immune cells, the researchers noticed that it looked similar to the fluid surrounding immune cells in the brain. It was filled with proteins that cause inflammation.
When they added the fluid to cultures of human cortical neurons, the team found that bead-like "swellings" soon began to grow along the axons and dendrites of the brain cells. Axons and dendrites are important for cell-to-cell communication in the brain.
Scientists have noticed these "neuritic beads" in the brains of patients with Alzheimer's disease and have suggested that they are an early sign of neuron damage. But it has not been clear what they have to do with abnormal tau or if they lead to Alzheimer's disease.
When they examined the neuritic beads, Prof. Cohen and colleagues found that they were made of accumulations of abnormal tau, but the form was different to that which is normally detected in Alzheimer's disease. Also, it would not be detectable with the tools that scientists normally use.
Tau detaches from microtubules
The researchers suggest that the different form of tau in the neuritic beads could be what causes it to become abnormal in Alzheimer's disease.
Normal forms of tau protein support microtubules, which are the long, parallel track-like structures that transport information molecules along the axons and dendrites.
However, in Alzheimer's disease, the tau proteins are detached from the microtubules and instead form clumps of long, thread-like tangles. While it is not clear whether the tangles themselves cause any harm, researchers have suggested that because the microtubules become denuded of tau, they lose their ability to transport information molecules.
The researchers suggest that abnormal tau in the neuritic beads could be the starting point for the protein's role in Alzheimer's disease.
They also found high levels of calcium in the neuritic beads. Too much calcium is known to harm brain cells and it is typically present in high levels in neurons of people with Alzheimer's disease.
Prof. Cohen says that they believe that the cascade of events following the inflammation responses "flood the neuron with calcium." The increase in calcium causes tau to change into an abnormal form.
"This probably leads to a snowball effect," explains Prof. Cohen, "tau detaches from microtubules and is trafficked throughout the neuron, ending up in these beads. One possibility is that these tau-filled beads are the sites where the classic tangle-like aggregates of tau will eventually emerge, which is the hallmark of Alzheimer's disease."
Further investigation revealed that a key protein called MMP-9 might be a trigger molecule for the cascade of events that leads to calcium influx and neuritic beading.
"MMP-9 is an inflammatory protein shown to be elevated in the brains of Alzheimer's patients," says Prof. Cohen.
He and his colleagues also identified another protein called HDAC6, which moves from inside neurons and accumulates in the beads.
Scientists believe that HDAC6 normally finds unwanted protein clumps inside cells and ferries them off for disposal. But when the team blocked HDAC6, it almost completely prevented the formation of neuritic beads.
Drug developers are already testing HDAC6 inhibitors and they are showing promising results, although exactly how they work has not been well understood.
Prof. Cohen suggests that their findings may help to explain why HDAC6 inhibitors are showing such promise, and they think that they may also help to "inform the development of other kinds of inhibitors that affect this cascade, particularly those that might impact cognitive processes."
The findings, as well as the idea of blocking HDAC6 and MMP-9, may also have implications for other neurodegenerative diseases that feature neuritic beading. The beading effect has also been seen following head injury and even in healthy brains. Perhaps it is an early mechanism in cognitive decline, Prof. Cohen suggests.
When the team examined aged mice, they found neuritic beads filled with tau. They also found that they could induce bead formation by triggering neuroinflammation in younger mice.
The researchers are already working on a mouse model to confirm and further study the "amyloid-to-inflammation-to-tau" cascade of events that they have identified.
"If we can demonstrate this cascade in a wild-type mouse, then we'll be able to study Alzheimer's and test therapies in ordinary lab mice without the need for artificial genetic engineering used in traditional Alzheimer's mouse models."
Prof. Todd Cohen