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Alzheimer victims may thank Kiran Bhaskar soon

July 18, 2019 18:52 IST

Rediff.com Senior Contributor P Rajendran reports from New York on how the Indian-American researcher's pioneering work may wipe out the visible effect of Alzheimer's disease.

Photograph: Kind courtesy StockSnap/pixabay.com

Kiran Bhaskar, a professor at the University of New Mexico, could not become a clinical doctor in India, but went on to complete his PhD there and now has come up with a vaccine that, at least in susceptible mice, wipes out the visible effect of Alzheimer's disease.

Most people know that Alzheimer's is a common form of dementia, marked by plaques, tangles of otherwise useful proteins, loss of nerve connections and brain inflammation.

It is also associated with damage to the hippocampus, a sea horse-shaped part of the brain important to memory and learning.

There is a longstanding argument that levels of amyloid beta, clumps of certain proteins, are linked to whether the disease shows up since amyloid is part of the plaques.

It got support from the fact that those with Down's syndrome, where there are three copies of chromosome 21 instead of the usual two, produce higher levels of amyloid beta.

Earlier, researchers thought amyloid beta levels in those with Alzheimer's may just not be able to undergo clearance at the same rate that it was produced.

But when low levels were also seen in Alzheimer's they conjectured it could have something to do with the ratio between a long and short forms of amyloid.

And so the theories continued.

All the while there was another protein lurking around in the neurofibrillary tangles that dodged attention -- tau.

"Amyloid is an earlier marker of Alzheimer's than tau," Dr Bhaskar told Rediff.com

"There was less interest in tau because it came up later in the disease progression."

 

Now normal tau is not a rogue protein.

It is believed to aid the function of microtubules, thin internal tubes that act both as a cell's internal struts and as bridges for caravans of chemicals crisscrossing it.

Yet, there it is in the neurofibrillary tangles.

Dr Bhaskar thought he could confirm the emerging view that warped tau proteins may not be just artifacts of Alzheimer's, but the proximate cause of the disease.

Dr Bhaskar considered ways to just remove them and do cognitive tests.

It helped that he had done his PhD work on the cell's cytoskeleton, post-doc research on tau proteins and, later, amyloid.

Dr Bhaskar and his team decided to use a virus that attack bacteria to get the immune system to target the tangles.

Such viruses, called bacteriophages, have been used since early in the last century to treat human illnesses, but fell out of favour in the West after the discovery of the antibiotic penicillin.

For his team's work, Dr Bhaskar relied on the work done by researchers in his department, David Peabody, Bryce Chackerian and others who had taken viral therapy a little further down the road, creating viral vaccines to target problematic protein segments, such as those found in nicotine or in Plasmodium, the single-celled creature that causes malaria.

Since the viruses used attacked only bacteria, it was safe to inject them into a variety of animals, including humans.

Since ethics boards do tend to frown on injections of germs or germ-like material into humans, the team relied on fully-grown otherwise normal mice, and rTg4510, a variety of mice that naturally produces high levels of abnormal tau.

The rTg4510 mice exhibit early signs of dementia, the effects being most prominent in two brain areas -- those behind the eyes and the temples, respectively.

Photograph: Kind courtesy Manuel Alvarez/pixabay.com

They plugged a phosphate group (phosphorus bonded to four oxygen atoms) to threonine, the 181st amino acid in the problematic tau protein.

This pT181 attached to the virus-like particle was the bait for the immune system to attack.

pT181 also tends to go up in the cerebrospinal fluid in Alzheimer's patients.

The plan was to inject the virus-like particle ferrying the pT181 a few times into the mouse.

When the immune attacked the virus-like particle, it would also generalize the attack to the pT181 already in the brain.

Often, research has this way of going wrong, even when all the bases appeared covered.

In that sense, the team led a relatively charmed life, though it had some trouble deciding on the right bit of pTau protein to attach to the virus-like particle.

"I think the only problem was with the rTg4510 mice," Dr Bhaskar said.

While Nikki Maphis was an experienced technician, her subjects were a little, well, demented in that they did exhibit the murine version of early onset Alzheimer's.

"It was hard to handle the mice. They were aggressive, jumpy. They were the only problems we faced," said Dr Bhaskar, concluding that the lesson they got from the experience was: "Stay away from these mice."

After three injections, given over six weeks, the mice were tested for their ability to recognize things they have seen before, and to find a geographic location.

To test for recognition, the researchers put each mouse in an open area for five minutes two days in a row with two identical glass jars.

The third day they added a novel object, a plastic water bottle.

If the mice still had dementia and so could not remember the glass bottles, they were likely to spend about equal time exploring the glass and plastic bottles.

If they spent more time with the novel object, that suggested they were already familiar with the glass bottles.

Gratifyingly for Dr Bhaskar and the others, the rTg4510 mice that had been vaccinated to get their immune system to attack pT181 in the tangles clearly preferred the novel plastic bottle to the glass ones.

Those that had received injections of the virus-like particle with no attached pT181 had trouble remembering the glass bottles they had seen the first two days.

Clearly, the immune systems in these control vaccinated mice were not trained to destroy pT181.

The 'normal' mice, which had no neurofibrillary tangles anyway, were not affected by the treatment they received.

The other test, called the Morris Water Maze, involved putting the mice in a drum of cold milky water with a small platform just beneath the surface that could hold them up.

Since the platform was not visible, the mice would have to rely on cues on the room's walls to swim to it and get some rest.

They were given four daily trials, each lasting about 25 minutes, for five days.

The platform was in a different quadrant for each mouse.

On the sixth day, the platform was diabolically removed.

If the bewildered mouse swam in the quadrant it had found the platform earlier, then it clearly knew where to look.

Again, the vaccinated rTg4510 did significantly better in this spatial memory task than their control vaccinated compatriots, and about as well as all the normal mice.

Brain samples supported the argument for the efficacy of the vaccine.

The pT181-virus particle vaccine reduces pTau in the hippocampus, that area involved with memory and spatial learning, and the cortex, which is linked to judgment, and to sensory, motor and cognitive skills.

The vaccination also prevented the shrinkage of the hippocampus and the corpus callosum, the latter being the bridge between the left and right halves of the brain.

Dr Bhaskar's team had a vaccine that worked -- even if it was only in mice.

If the results can be replicated in humans, an Alzheimer's diagnosis will no longer be the debilitating death sentence it is today.

Clearly, it is a very good thing Dr Bhaskar did not become a clinical doctor.

IMAGE: Dr Kiran Bhaskar, a professor at the University of New Mexico. Photograph: Kind courtesy Dr Kiran Bhaskar

His parents Bhaskar Sundaraiah and Nagarathna Davanagere, despite being nurses, did not know about graduate programmes he could take but encouraged him to keep learning.

Dr Bhaskar went to college at the University of Mysore.

After missing out on medical school in the hypercompetitive environment, he earned his bachelor's and master's there, and then headed for the National Institute of Mental Health and Neurosciences in Bengaluru to earn a PhD in neurophysiology.

He did postdoctoral studies at the University of Iowa, and worked at the Cleveland Clinic before becoming an assistant professor at UNM in 2012.

"My interest really took off in NIMHANS," he said, describing the focus there on many brain diseases that had no cure.

"It was the only best institutions for neuroscience research in India back in early 1990s."

He particularly remembers the mentorship of Professors Taranath Shetty and Ramamohan there.

Despite his years away from India, Dr Bhaskar keeps strong ties with his homeland and perhaps rues having to work elsewhere.

"If India can encourage and keep talent, stimulate people to stay in India, it would help," he said.

"Although I left several years ago, I got my US citizenship in 2015."

He harks back to a speech Prime Minister Narendra Damodardas Modi gave while in the US.

"Modi said he would encourage dual citizenship. That would ensure people like us are not left out," he said.

His wife Anupama Suryanarayana, who has a master's degree in biochemistry, works in a start-up. They have two children: Aditya 12, and Ahana, 8.

 

P RAJENDRAN / Rediff.com
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