Tanz research uncovers how immune cells contribute to synapse weakening in earliest stages of Alzheimer’s disease
Researchers at the University of Toronto’s Tanz Centre for Research in Neurodegenerative Diseases have uncovered a link between neuronal receptor proteins and brain immune cells that may help explain damage to the brain in the earliest stages of Alzheimer’s disease.
Graham Collingridge, director of the Tanz Centre and professor in the department of physiology at U of T’s Temerty Faculty of Medicine, led the research, which was published in iScience earlier this month.
Synapses, the connections between neurons in the brain that are responsible for learning and memory, can become stronger or weaker over time, a process known as synaptic plasticity. Synapse weakening is a normal physiological process that “frees up” the brain to learn and retain new information, but scientists believe that when the balance between strengthening and weakening shifts in favour of weakening, neurodegeneration can occur.
“In the brains of people with Alzheimer’s disease, the normal physiological mechanisms that weaken synapses get out of control and synapses are lost. If the synapses aren’t restored, the neurons die, and that’s when you start to see the hallmark features of amyloid beta protein plaques and tangles,” says Collingridge, who is also a senior investigator in the Lunenfeld-Tanenbaum Research Institute, part of Sinai Health.
“It used to be thought that these plaques and tangles were the cause of neurodegeneration, but increasingly more scientists view them as markers of late-stage disease. They signify that neurodegeneration has happened, but they don’t necessarily cause it.”
In Collingridge’s research program at the Tanz Centre, his team investigates synaptic plasticity, specifically how proteins on cell surfaces called receptors are involved in the process. Two types of glutamate receptors on the synapses, mGlu5and NMDA, are important for communication in the brain and seem to have roles in synaptic weakening and Alzheimer’s disease, though scientists haven’t understood how.
At the same time, immune cells in the brain called microglia may also have a role in Alzheimer’s disease. Microglia are important in cleaning up weakened synapses, but if they become overactive, they can attack healthy synapses, leading to neurodegeneration.
Both the receptors and microglia appear to have roles in synapse weakening and Alzheimer’s disease, but scientists haven’t understood how these factors are related. In Collingridge’s recent study, his Toronto team, in collaboration with scientists at the University of Bristol (UK), investigated a potential link between these synapse receptors and microglia to understand the mechanisms that trigger excessive synapse weakening, the earliest stage in Alzheimer’s disease.
In models of the disease, the team used a pharmacological compound to activate the mGluR receptor. They then examined the impact of activating this receptor on an immune cell communication pathway called the complement cascade, to understand how the neurons and microglia communicate.
Collingridge’s team uncovered a direct line of communication between neuronal receptors and microglia in an experimental model of Alzheimer's disease. They found that oligomeric amyloid beta, thought to be a toxic molecule that builds up in the brains of people with Alzheimer’s disease, enhances synaptic weakening by a process that engages microglia. The underlying mechanism was shown to involve the neuronal mGlu5 receptors and NMDA receptors and a component of the immune system, called complement C5a receptors.
“Scientists have speculated that microglia and synaptic weakening are linked, but this may be the first evidence of it being linked through this particular complement cascade protein,” explains Collingridge.
The study helps to explain the mechanisms that lead to the synaptic weakening and cognitive decline seen in people with Alzheimer’s disease, which is critical for designing effective therapies.
“If we want to develop effective therapies, then we need to understand what’s happening at the earliest stages of the disease. A lot of current effort in the field is focused on the tangles, but in our opinion, this isn’t particularly informative because we see these as gravestones for synapses that have already died. We want to understand what is happening early on in the disease,” says Collingridge. “The more we understand the basic biology and how that gets affected in Alzheimer’s disease, the more opportunities there are for novel therapeutic strategies.”
Collingridge says that this new study builds on previous work by researchers at the Tanz Centre that showed gene mutations commonly found in people with Alzheimer’s disease were linked to microglia.
“Previous work of Tanz scientists several years ago identified the important role of microglia in Alzheimer’s disease,” says Collingridge. “Building upon this, we now have been able to identify a potential mechanism by which microglia contribute to the aberrant weakening of synaptic connections, an early stage in neurodegenerative diseases.”
