Decoding Dementia

Brain researchers in NTU are connecting circuits to conditions.

As populations in developed countries around the world begin to age, neurodegenerative diseases such as dementia will increasingly come to the fore. In fact, the World Health Organisation predicts that neurodegenerative diseases will overtake cancer to become the second leading cause of death by as soon as 2040. “In 2018, dementia affected 50 million people worldwide. By 2050, that number is projected to reach beyond 150 million,” says Prof Lim Kah Leong, a neuroscientist and Parkinson’s disease expert at NTU’s Lee Kong Chian School of Medicine and the School’s Vice Dean (Research).

Beyond the sheer numbers, dementia exerts a heavy toll on sufferers and caregivers alike. “Every single case is a really debilitating situation,” says Prof George Augustine, the inaugural Irene Tan Liang Kheng Chair Professor in Neuroscience at NTU’s joint medical school with Imperial College London. “These are people who lose their very selves, which in itself is tragic. Furthermore, they put high demands on their families and society at large for support.”

In anticipation of the needs of Singapore’s rapidly ageing population, Prof Augustine is working with Prof Lim and 15 other principal investigators on the brain circuitry of dementia, having been awarded a grant of S$19.4 million (US$14.2 million) from the Singapore government.

The five-year consortium project, which will receive additional support from NTU in the form of laboratory space and salaries for graduate students and post-doctoral fellows, will focus on four main brain disorders leading to dementia, namely: Alzheimer’s disease, Huntington’s disease, frontotemporal dementia and Down syndrome.

Seeing the brain in a new light

One of the biggest challenges in studying neurodegenerative diseases such as dementia is that the brain is an incredibly complex organ. The human brain has about 86 billion brain cells or neurons, each of which can form an average of 7,000 connections. Identifying which of these hundreds of trillions of connections are involved in dementia is many times more difficult than finding a needle in the proverbial haystack.

“The fundamental problem with studying the brain is an embarrassment of riches,” Prof Augustine says. “What we need to do is to be able to selectively interrogate individual elements within the circuit. Optogenetics allows us to do just that by taking advantage of the capabilities of optics and genetics.”

Discovered a decade ago by Karl Deisseroth at Stanford University—once a student of Prof Augustine—optogenetics lets scientists precisely control the neurons they are interested in using light. To do this, neurons are genetically engineered to express a light-sensitive protein so that they can be activated and inactivated using light. “Since no other neurons in the brain care about the light, we can be very sure that when we shine light on the brain we are only activating one kind of neuron rather than the hundreds or thousands of other kinds of neurons that are in the mix,” Prof Augustine explains.

Optogenetics allows mapping of the circuit structure between inhibitory neurons (green) and an excitatory neuron in the hippocampus (red). Triangular structure on the right: glass pipette to fill the neuron with red fluorescent dye. Credit: Ryuichi Nakajima/George Augustine.

The first objective of the project, he continues, is to use the game-changing potential of optogenetics to map out the circuits and parts of the brain associated with dementia. “Our goal is to use the technology we have developed to look at circuitry defects in several different animal models of dementia,” Prof Augustine says.

From circuits to behaviour

Mice, in particular, could play an important role in unravelling the complexities of dementia. Not only are they mammals with a physiology similar to that of humans, they also exhibit behaviours that can be linked to experimentally-induced circuitry changes. “This is something that in vitro models, including patient-derived human cells, could not reproduce,” says Prof Lim, who leads the animal models team.

Nonetheless, Prof Lim cautions that no single model can reflect the entire biology of a disease as complex as dementia, noting that existing mouse models tend to show either accelerated disease progression or only very subtle symptoms. “For these reasons, the dementia team at the medical school is working on an Alzheimer’s disease mouse model that expresses the human disease entity at a more physiological level and at appropriate predilection sites of the brain.”

One of the dementia-linked behaviours that the researchers are interested in is memory loss, shares Assoc Prof Ajai Vyas, a behavioural biologist at NTU’s School of Biological Sciences who leads one of the three teams supported by the grant. “When the other teams discover circuits that are likely to be involved, we can do behavioural tests to see if we can recreate the symptoms in wide-awake, behaving animals. Our results then inform the work of others studying the circuits and the molecular level in a reciprocal way.”

Once the circuit defects associated with dementia have been validated and linked to behavioural problems, the researchers plan to do a deep dive into the cellular and molecular mechanisms behind the circuit defects, says Prof Augustine. “Just showing that there are defects is important, but the next step—which is especially important for thinking about how to cure dementia—would be to figure out what exactly causes the circuit defects.”

Structure of a neuron in the claustrum, a part of the brain potentially involved in consciousness. Credit: Martin Graf/George Augustine.

While finding a cure is the Holy Grail of dementia research, the journey from the lab to the clinic will inevitably be a long and fraught one, Prof Augustine says. “I think it is safe to say that we will not cure dementia within a five-year timeframe,” he adds. “More realistically, we will learn important new things about dementia because we are the only people looking at dementia from a circuitry perspective. I am confident that what we learn will be of fundamental importance for figuring out dementia.”

Finding common ground

The reason that looking at the circuitry of dementia is a beneficial research direction, says Prof Augustine, is that it allows us to uncover common themes across diverse diseases. “The problem is that everyone is siloed; people studying Alzheimer’s disease only think about dementia from an Alzheimer’s perspective. Similarly, people studying Huntington’s disease or Down syndrome are siloed, not only in thinking predominantly about their own disease but also in limiting their perspective to certain kinds of experimental observations, hypotheses and ideas.”

“We are intentionally cutting across silos by looking at conditions where the only thing that they really share is dementia,” Prof Augustine says.

“Importantly, we are looking at defects in the neural circuitry of different dementia models, with the view to elucidate a shared circuitry signature among them that could represent a common denominator underlying cognitive impairments,” adds Prof Lim, who is a member of Singapore’s National Neurosensory Task Force and a chair of its subpanel on ageing-related diseases and complications.

But beyond the technical benefits of this interdisciplinary approach is the additional “soft” benefit of building a collaborative research culture within Singapore’s neuroscience community. “The main reason I’m here in Singapore, in my opinion, is to connect people together,” says Prof Augustine, who has been in Singapore for the past 11 years after leaving his previous position at Duke University in the US. “There are pockets of excellence in neuroscience throughout the country. Now that we have the money to put behind our collaborations, it increases everyone’s commitment,” adds Prof Augustine, who is also a member of the programme in neuroscience and behavioural disorders at the Duke-National University of Singapore (NUS) Medical School.

“The grant project led by Prof George Augustine has provided me with the necessary resources to embark on exciting research,” says Prof Lim. “It also helped to bring together the local neuroscience community working on dementia.” In particular, Prof Lim shares that the frequent discussions with team members from NTU’s medical school and other schools in the University, as well as partners at NUS and Singapore’s National Neuroscience Institute, have taught him a great deal. “I have personally benefitted from the cross-fertilisation of ideas,” he says.

“We have also had the chance to interact with our overseas colleagues who are experts in dementia research. All this has helped to enhance our international visibility,” Prof Lim concludes.

The article appeared first in NTU’s research & innovation magazine  Pushing Frontiers (issue #16, February 2020).