Against the backdrop of an aging population, neurodegenerative diseases causing various types of dementia, such as Alzheimer's disease, are predicted to double every 20 years.
One of the challenges in curing Alzheimer's is solving the riddle of why the brain's own immune system misfires in response to the beta-amyloid proteins that form plaques in the brain. These plaques initiate a cascade of events that lead to the disruption and eventual death of neurons, resulting in cognitive decline.
"We're exploring what goes wrong with the brain's immune response such that it can no longer control the pro-inflammatory signals driven by the continual accumulation of beta-amyloid plaques and why it goes awry," said Greg Dekaban, chair of microbiology & immunology at Schulich School of Medicine & Dentistry at Western University. "We're trying to get a more complete understanding of the underlying inflammatory processes in the brain associated with Alzheimer's disease that often take on a 'double-edged sword' nature, where the inflammatory immune response can be beneficial at one point, but then turn harmful."
The research team includes Marco Prado, Vania Prado and Jane Rylett from Schulich Medicine & Dentistry and Greg Fonseca, a scientist in the Translational Research in Respiratory Diseases Program at the Research Institute of the McGill University Health Centre (RI-MUHC) in Montreal. They have been awarded a $2.4 million grant from the Krembil Foundation for a three-year project titled Determining Why Immune Regulation Fails to Control Neuroinflammation in Alzheimer's Disease.
Normally, an inflammatory response drives restorative processes in the brain, said Dekaban - but in Alzheimer's there seems to be a switch that triggers a loss of control of the inflammation. Dekaban's team is looking for the 'switch.'
"Compounding our problems is that Alzheimer's, like many chronic diseases, progresses non-uniformly in the brain," added Fonseca. "That means while some areas have obvious disease, others may have no disease or disease that is difficult to see, due to non-uniform inflammatory responses. Looking at all of these areas at the same time averages the results, potentially hiding disease. Because of this, we have to use spatial data to show the location in the brain, along with machine learning models to analyze inflammation."
The work may reveal new therapeutic targets that could accentuate the immune response and enable it be more efficient and - just as importantly - identify when intervention needs to start in order to arrest the progressive nature of Alzheimer's disease.
An additional challenge the team faces is understanding the impact of the aging process in the development of Alzheimer's.
"This is a disease of aging and we know that, as you age, your immune system becomes less efficient and less competent," Dekaban said. "We're trying to understand if the immune system changes with age in such a way that the signals that used to be there when we were younger disappear or become weaker as we grow older."
Working with the MouseTRAP (Mouse Translational Accelerator Platform), a Western-led facility to accelerate drug discovery for neurodegenerative diseases, the team will use mouse models to follow the immune responses of the brain over a two-year period and look for specific signals that result in the misfunction of the immune system.
Dekaban's current work is based on an earlier Canadian Consortium on Neurodegeneration in Aging (CCNA)-funded project that looked at the role of beta-amyloid plaques in the development of the disease. These plaques trigger subsequent processes that lead to the eventual death of neurons and the loss of cognitive function seen in Alzheimer's disease.
The Krembil Foundation
The Krembil Foundation is a Canadian family-led non-profit organization which supports medical research. The goal of the Foundation is to accelerate research, expand knowledge and ultimately impact lives through discoveries that will lead to scientific advancements in medicine. With this goal in mind, the Foundation focuses its funding on areas that have been historically underfunded: neurodegenerative diseases, and autoimmune diseases. The Foundation supports research with the intention of bridging gaps in knowledge, and ultimately helping discover treatments and cures for neurodegenerative diseases.
