Research Profile - Slow and steady wins the race

It's slow, tedious work, sorting through literally thousands of genes, looking for the one that will make a difference in a disease like Alzheimer's. But it's also necessary work – and work that wasn't possible just 10 years ago.

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This work could pave the way toward a therapy that does more than simply treat the symptoms of Alzheimer's disease, but that can actually stop the progression of the disease in its tracks.

That's the ultimate goal of Dr. Lili-Naz Hazrati, a neuropathologist at the Toronto General Hospital/University Health Network and principal investigator at the Tanz Center for Research in Neurodegenerative Diseases. She's taking a bit of a different approach toward achieving her goal, however.

Most research on Alzheimer's disease focuses on the neurons that die as a result of the disease. Dr. Hazrati is focusing on the synapses, the connections between neurons that enable them to communicate with each other.

"As we learn and grow from babies to adults, it is because synapses get stronger," she says. "What makes us who we are is the communication between our neurons."

And while the damage that Alzheimer's does to neurons is visible – the misfolded amyloid and tau proteins –
Dr. Hazrati thinks that this damage may start in the synapses.

"There's no question that the amyloid and tau proteins are a big part of the disease," she says. "But brains are so complex and there's a lot we can't see. The damage from these proteins could actually be the end point, the result of other changes we don't see."

With the help of funding from the Canadian Institutes of Health Research, Dr. Hazrati is using multiple technologies from the field of proteomics, the study of protein structure and function, to examine something called mRNA, or messenger RNA. This molecule plays an important role in the body, carrying with it instructions for specific proteins. She is determining which mRNAs are active in healthy mice and then seeing which are present and which are absent in mice genetically modified to develop a mouse form of Alzheimer's disease – something she couldn't have done even 10 years ago, because the technology simply didn't exist.

"It's a fishing expedition," she says. "But once we have the differences, we can track them and see what difference they make."

Another essential part of the task will be to find out how the proteins and genes she and her team identify work with the amyloid and tau proteins that are part of the visible aspect of Alzheimer's disease.

It's time-consuming work, says Dr. Hazrati, with every step needing to be done at least twice to validate the findings. But once it's done, they will have solid targets for interventions.

"If you didn't do it this way, you may end up on a wrong path," she says. "If you can't validate and have an effect on the disease itself, we're going nowhere."

The Study

Loss of communication between neurons is a characteristic of most neurodegenerative diseases, including Alzheimer's disease. This communication is carried out by synapses and the loss of synaptic structure is the most fundamental change in neurodegenerative diseases, encompassing the loss of brain function. There is a lot we don't know about the mechanisms underlying the collapse of synapses, a phenomenon that is often seen as the consequence of other changes, such as overall neuronal death. Dr. Lili-Naz Hazrati is using emerging technologies from imaging, molecular science and proteomics to study the underlying mechanisms leading to the loss of synapses. A better understanding of these processes is essential for the design of effective treatment and preventive strategies for many neurodegenerative diseases, including Alzheimer's disease.

"As we learn and grow from babies to adults, it is because synapses get stronger. What makes us who we are is the communication between our neurons."
- Dr. Lili-Naz Hazrati, Toronto General Hospital/University Health Network