Does Brain Inflammation Trigger Neurodegeneration? If So, it Could Open the Door for New Therapies

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Today, more than 6 million Americans suffer from neurodegenerative diseases such as Parkinson’s, Alzheimer’s, and multiple sclerosis, and as our society ages, that number is only going to go up. If left unchecked for 30 years, more than 12 million will be affected.

 Economically, the statistics are just as bad. In 2018, Alzheimer’s alone cost the United States $277 billion, which could rise to $1 trillion by 2030.

Most patients with these diseases have no effective treatment options, and it is clear that new approaches to therapeutic development are needed. Interestingly, recent research has shown that inflammation in the brain may trigger neurodegeneration, and a new study from NYSCF Senior Research Investigator Valentina Fossati, PhD, in collaboration with New York University’s Shane Liddelow, PhD, finds the first evidence of this phenomenon in human cells.

At a recent webinar held as part of NYSCF’s Virtual Learning and Events Program, Drs. Fossati and Liddelow were joined by Johns Hopkins’ leading neuroimmunologist Peter Calabresi, MD, to talk about the benefits and detriments of inflammation, how it factors into neurodegeneration, the importance of diversity in disease research, and what all of this means for new therapies. The discussion was moderated by NYSCF’s Associate Vice President of Scientific Outreach Raeka Aiyar, PhD.

Inflammation: A Double-Edged Sword

Inflammation in the body is usually a helpful defense mechanism against injury and disease, but when it goes awry, it can have disastrous consequences.

“We think about inflammation as being the body’s response to injury, and it is typically good: it’s the body trying to clear an infection or heal tissue,” explained Dr. Calabresi, Director of the Division of Neuroimmunology and a Professor of Neurology at Johns Hopkins, where he also treats patients with multiple sclerosis. “The problem is when the immune system either doesn’t shut off, or it makes a mistake and it attacks its own proteins thinking that they are foreign invaders.”

The ‘not shutting off’ part is what tends to wreak havoc in neurodegenerative diseases.

“Inflammation can be good for fighting viral infections, but it can also be dangerous because inflammation can expand the brain into the skull,” added Dr. Liddelow, an Assistant Professor of Neuroscience and Physiology and of Ophthalmology at NYU. “And in the context of diseases like Alzheimer’s or multiple sclerosis, the problem is not necessarily that inflammation begins, but that it doesn’t stop, and the stopping is what’s important.”

For a timely example of how dangerous overactive inflammation can be, look to COVID-19.

“There are some cases where inflammation can get out of control and then starts to be harmful instead of helpful,” said Dr. Aiyar. “For example, in severe COVID-19, cytokine storms can take over and cause harm.”

In ‘cytokine storms’ the immune system releases lots of pro-inflammatory molecules which begin to damage the body rather than heal it.

“In the setting of COVID, the immune system is desperately trying to keep up…and it sometimes responds overexuberantly,” noted Dr. Calabresi. “So, while suppressing the immune system early on might be a bad thing, during the late stages of the inflammatory cytokine storm, it may be an appropriate therapy. We need to understand this process in the context of degenerative diseases so that we can target the pathogenic aspects of the immune cells without compromising their beneficial effects.” 

When Good Cells Go Bad

 When inflammation doesn’t shut off in neurodegenerative diseases, it can turn a typically helpful category of brain cells into neuron-killers.

“Neurons are our communicators, and they’re really good at their jobs, but they need the help of other cells in the brain, which are collectively called glia,” explained Dr. Fossati.

“I like to go to the opera, and I like to think of the neurons as the opera singer: they get all of the glory. They’re really exciting, but behind that you have all the glial cells, which are the engineers that make the building, the subway that gets you there on time, the traffic warnings, the babysitters, and so on,” added Dr. Liddelow. “And unfortunately, in the context of disease, they may also be the Mafia.”

“We are discovering more and more that when you have a neurodegenerative disease, something goes wrong, and glia can turn from supporters into murderers: they can literally kill the neurons,” said Dr. Fossati. “And we are seeing that inflammation could be involved.”

Specifically, a previous study from Dr. Liddelow found that in disease-like, inflammatory environments, astrocytes in mice can ‘go rogue,’ killing the neurons they usually support. In their new study, featured this month on the cover of Neuron, Drs. Fossati and Liddelow saw that this was also happening in human cells.

“We turned patient stem cells into astrocytes and saw that they killed stem-cell-derived neurons from the same patient in disease-like environments,” remarked Dr. Fossati. “This is incredibly exciting because it opens up entirely new avenues for therapeutic interventions that target this process.”

Dr. Calabresi echoed this enthusiasm, citing stem cells as a major advantage for understanding the complex underpinnings of neurodegeneration.

“I can’t emphasize enough how frustrating it has been as a neurologist to not actually be able to study the target organ [the brain]. In many diseases, we can biopsy tissue or organs and study them right from the onset of the disease, but in a disease like multiple sclerosis, or any of the brain diseases, we really don’t want to take a piece of brain tissue,” he said. “So, having the capacity to take blood cells from my multiple sclerosis patients and then use Valentina’s protocols to convert them into brain cells and study glia is revolutionizing our ability to tease apart the biology of these diseases.” 

Diversity: The Key to Precision Medicine

The panelists agreed that while these findings are exciting for the future of drug development, we have to keep in mind that to truly find treatments that work for everyone and enable precision medicine, research must include ethnically diverse groups of patients. 

“It was said several decades ago that MS was a white person’s disease, and that couldn’t be more wrong,” remarked Dr. Calabresi. “One of the ways we’ve been studying this is by quantifying the health of nerves in the back of the eye…We find that our Black patients seem to have degeneration at a rate that is double the average of white patients. We’re interested in studying the biology of this using iPSC-derived glia.”

NYSCF has established a partnership with Johns Hopkins and Bloomberg Philanthropies to advance precision medicine, which includes examine neurodegenerative diseases across diverse ethnic groups.

“I’m very lucky to work at NYSCF because we are very much committed to trying to represent as many ethnicities as we can in our research,” added Dr. Fossati. “NYSCF has built automated platforms to generate stem cell lines at a large scale. This has completely shifted the way we study diseases like MS where looking at one or two patients doesn’t really tell you much – you need to look at a broader population. That’s why I am incredibly excited about the collaboration that we’re starting with Dr. Calabresi and Johns Hopkins, where we can focus on expanding our cohort to cover all the different ethnicities.”

New Hope for Neurodegenerative Disease Therapies

Altogether, the panelists believe that studies of inflammation and neurodegeneration will bring about much-needed therapies.

“It’s an incredibly exciting time and being able to study the biology of glial cells, identify targets, and develop drugs that will turn off the deleterious inflammation, but hopefully preserve the beneficial inflammation,” said Dr. Calabresi. “I think that is going to be hugely important for all neurodegenerative diseases…It makes perfect sense to me that the astrocytes and the other glial cells are mediating this toxicity.”

“To have two new cell types that you can target with multiple different possible reactors is very exciting,” agreed Dr. Liddelow. “We have the option and the ability now to really go after this.”

“I think it’s time for cautious optimism because none of the drugs available now have targeted glia cells. We have a completely new door that opened up with this study,” said Dr. Fossati. “It’s not going to be easy and it’s not going to be tomorrow, but for the first time in I think one hundred years, we have completely new targets, and that’s very promising to me.”

Watch the full discussion below.