Researchers may have discovered the ‘ground zero’ of Alzheimer’s disease, paving the way to treatment that could halt condition in its tracks.
A team of scientists at the University of North Carolina’s Medical School conducted a series of experiments to look at different factors driving the disease in order to try and pinpoint a way to stop it in its tracks.
Alzheimer’s disease causes abnormal deposits of amyloid beta protein and tau protein in the brain, as well as swarms of activated immune cells.
The team of researchers used different experiments to look at how the proteins and activated immune cells attack the brain and cause Alzheimer’s-related symptoms.
They also found that one medicine currently in development that blocks a specific protein – HDAC6, which originates from within neurons – show progress in preventing the damage that causes those symptoms.
The drug, called tubastatin A, is currently undergoing late stage clinical trials at a number of hospitals around the United States.
Scientists at the UNC’s Medical School conducted a series of experiments to look at different factors driving the disease in order to try and pinpoint a way to stop it in its tracks (stock image shows amyloid beta peptide in the brains of Alzheimer’s patients)
Led by Dr Todd Cohen, assistant professor of neurology, UNC scientists used human cell cultures to show how amyloid beta can trigger a dramatic inflammatory response in immune cells and how that interaction damages neurons.
The team then showed how that kind of neuron damage leads to the formation of bead-like structures filled with abnormal tau protein.
Similar bead-like structures are known to form in the brain cells of people with Alzheimer’s disease.
The UNC researchers also identified two proteins – MMP-9 and HDAC6 – that help promote this harmful, amyloid-to-inflammation-to-tau cascade.
These proteins and others associated with them could become drug targets to treat or prevent Alzheimer’s.
‘It’s exciting that we were able to observe tau – the major Alzheimer’s protein – inside these beaded structures,’ said Dr Cohen, who is also a member of the UNC Neuroscience Center.
‘We think that preventing these structures from forming would leave people with healthier neurons that are more resistant to Alzheimer’s.’
RESEARCHERS SHOWED HOW NEURONS ARE DAMAGED IN PEOPLE WITH ALZHEIMER’S
ALZHEIMER’S: FAST FACTS
WHAT IS IT?
Alzheimer’s disease is a progressive, degenerative disease of the brain.
A build-up of abnormal proteins causes nerve cells to die.
This disrupts the transmitters that carry messages, and causes the brain to shrink.
As brain cells die, the functions they provide are lost.
That includes memory, orientation and the ability to think and reason.
The progress of the disease is slow and gradual.
On average, patients live five to seven years after diagnosis, but some may live for ten to 15 years.
- Loss of short-term memory
- Behavioral changes
- Mood swings
- Difficulties dealing with money
- Difficulties making a phone call
- Difficulties following a TV show
- Severe memory loss, forgetting close family members, familiar objects or places
- Becoming anxious and frustrated over inability to make sense of the world…
- …This can lead to aggressive behavior
- Eventually lose ability to walk
- May have problems eating and drinking
- The majority will eventually need 24-hour care
HOW ALZHEIMER’S DIFFERS FROM NORMAL MEMORY LOSS:
With ordinary age-related forgetfulness, you will still remember details associated with the thing they’ve forgotten.
For example, you may forget your neighbor’s name in conversation, but you still know that person is your neighbor.
Alzheimer’s sufferers forget the entire context.
To begin the study, Cohen and colleagues exposed immune cells normally found in an activated, inflammatory state in human Alzheimer’s brains to tiny clusters of amyloid beta – or oligomers, which are believed to be the most harmful forms of the protein.
‘Our thinking was that the amyloid beta oligomers would activate an inflammatory response in these immune cells, as prior research suggested, and we wanted to see if this would induce pathological forms of tau when given to neurons,’ Dr Cohen said.
The researchers then focused on the fluid in which the immune cells had been growing.
This fluid, which was filled with inflammatory factors – or proteins – resembled the fluid in which these cells typically live inside human brains.
The team added this fluid to cultures of human cortical neurons. The neurons soon developed abnormal, bead-like swellings along their axons and dendrites.
Axons and dendrites are on either side of a neuron – dendrites bring information into the cell body, and axons send it out into another cell.
This ‘neuritic beading’ on axons and dendrites has been seen in Alzheimer’s patients and has been considered an early sign of neuronal damage, although it hasn’t been clear how beading was connected to abnormal tau or if the beading led to Alzheimer’s disease.
The researchers then looked for tau in the beads and found a striking accumulation of it, though it was in an abnormal form and undetectable with the usual tools scientists use to detect the type of tau typically seen in Alzheimer’s patients.
Instead, the beaded tau was modified in a different way than previously thought. This modification is what causes tau to become aggregated, Dr Cohen said.
Tau proteins normally provide structural support for long, railway-like structures called microtubules, which are used to transport key molecules along axons.
For reasons that have never been clear, tau proteins in Alzheimer’s-affected neurons have a different pattern.
They are detached from microtubules, bear abnormal chemical modifications, and clump into long, tangled, and thread-like aggregates.
Whether these tau aggregates actively harm neurons isn’t clear, but prior studies suggested that the loss of tau from microtubules and resulting disruption of axonal transport might cause serious damage.
The finding of abnormal tau in the neuritic beads indicated that these beads could mark tau’s entry into the Alzheimer’s disease process.
Within the beads, Dr Cohen’s lab also found high calcium levels, which are known to harm neurons and are considered an important feature of neurons in people with Alzheimer’s.
‘We think these neuroinflammatory factors trigger this cascade,’ Dr Cohen said.
‘They flood the neuron with calcium. And we think that once the calcium accumulates, it causes tau to become abnormally modified.
‘This probably leads to a snowball effect: 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.’
A team led by collaborating researcher Dr Xian Chen, associate professor of biochemistry and biophysics at UNC, used mass spectrometry to sort out the amyloid beta-induced neuroinflammatory molecules that had triggered the calcium influx and neuritic beading.
RESEARCHERS IDENTIFIED TWO PROTEINS THAT HELP PROMOTE THE BUILDUP OF AMYLOID BETA IN THE BRAIN
EYE TEST COULD SPOT ALZHEIMER’S DISEASE 20 YEARS BEFORE SYMPTOMS
An eye test could spot Alzheimer’s disease two decades before symptoms emerge, a new study claims.
Researchers in Los Angeles trialed the test on 16 patients.
Comparing their results to brain scans, the eye test was just as successful at spotting those with twice the amount of plaque build-up in their brains.
Experts say the finding is one of the biggest breakthroughs in Alzheimer’s research to date, offering the first sign of a cost-effective and non-invasive test.
Until about a decade ago, the only way to officially diagnose someone with Alzheimer’s disease was to analyze their brain posthumously.
In recent years, physicians have been able to use positron emission tomography (PET) scans of the brains of living people, to identify markers of the disease.
However, the technology is expensive, and the test is invasive, since the patient needs to be injected with radioactive tracers.
Dr Koronyo-Hamaoui’s team set out to identify a more cost-effective and less invasive technique.
The Cedars-Sinai research team collaborated with investigators at NeuroVision Imaging, Commonwealth Scientific and Industrial Research Organisation, University of Southern California, and UCLA to translate their noninvasive eye screening approach to humans.
For the study, the researchers conducted a clinical trial on 16 AD patients who drank a solution that includes curcumin, a natural component of the spice turmeric.
The curcumin causes amyloid plaque in the retina to ‘light up’ and be detected by the scan.
The patients were then compared to a group of younger, cognitively healthy individuals.
The researchers found their results were as accurate as those found via standard invasive methods.
The team was able to show that one protein in particular, MMP-9, was responsible for some of this adverse effect.
‘MMP-9 is an inflammatory protein shown to be elevated in the brains of Alzheimer’s patients,’ Dr Cohen said.
‘In our study, we show that MMP-9 alone can trigger a calcium influx that floods the neuron.’
The researchers also identified the protein HDAC6, which originates from within neurons and concentrates in the neuritic beads.
Normally, HDAC6 is thought to detect unwanted protein aggregates within neurons and transport them away for disposal. However, blocking the protein stopped nearly all beads from forming in Dr Cohen’s lab experiments.
Both of these proteins have been found to be elevated in affected areas of Alzheimer’s brains.
Drug companies are now developing and testing HDAC6 inhibitors, which have performed surprisingly well in early studies, although it has not been fully understood how these inhibitors work.
‘Our work might explain why HDAC6 inhibitors have shown such early promise,’ Dr Cohen said.
‘And we think our work can help inform the development of other kinds of inhibitors that affect this cascade, particularly those that might impact cognitive processes.’
A therapeutic strategy to block HDAC6 or MMP-9 might have applications beyond Alzheimer’s.
Neuritic beading is seen in several other neurodegenerative diseases as well as after head injury.
Scientists have even observed beading to small extents in seemingly healthy elderly brains. Beading might be a general mechanism underlying cognitive decline, Dr Cohen said.
In their study, Dr Cohen and colleagues found some tau-filled neuritic beads in the brains of aged mice. And they discovered that chronic neuroinflammation could induce the beads to form in younger mice.
The researchers are now focused on creating a mouse model to confirm and further investigate the amyloid-to-inflammation-to tau process seen in this Cell Reports study.
‘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,’ Cohen said.