There are over half a million Canadians living with dementia. Treatment of this devastating disorder is challenging as there are no drugs available to cure it. Developing a new drug, running clinical trials, and acquiring approval from regulatory agencies is expensive and time-consuming: the process can take decades and cost upwards of 4 billion dollars.
Prof. Praveen Nekkar with PhD candidate and one of the study's co-author Amy Phan.
To avoid these barriers, Praveen Nekkar, a professor at the School of Pharmacy at Waterloo, is exploring drug repurposing – the practice of determining new therapeutic uses for drugs that are already approved by regulatory agencies. Nekkar and his group examined a class of drugs called selective serotonin uptake inhibitors (SSRIs). These drugs are typically used in conditions like depression. Nekkar’s team found that they can also play a role in preventing the progression of Alzheimer’s.
“If we can determine novel applications for drugs that have already been approved and demonstrated to be safe, we can expedite the process of providing safe and effective treatment to people with Alzheimer’s,” said Nekkar. “We chose to examine FDA-approved SSRIs because about 40 to 50 per cent of people diagnosed with Alzheimer’s are also diagnosed with depression and take SSRIs. Secondly, the chemical structure of SSRIs suggested they would be likely to interact with the protein that causes Alzheimer’s.”
Alzheimer’s disease is a progressive condition that worsens over time. It can occur when amyloid-beta proteins in the brain clump together and form plaques. These plaques block cell-to-cell signals, resulting in delayed cognitive function. As these plaques grow, the brain’s ability to make connections and send and receive information is further impaired.
Nekkar and his team demonstrated that SSRIs can delay the development and growth of these amyloid-beta plaques. To determine this, they tested amyloid-beta in the lab, experimenting with the type and amount of SSRIs. The team found that SSRIs delayed amyloid-beta from binding together to form fibrils – the larger protein aggregates that make up plaques. In particular, two types of SSRI were very effective at preventing binding.
The above shows how a type of SSRI binds to a string of amyloid beta. By taking up this binding spot, the SSRI prevents the proteins from clumping together to form fibrils.
“These are promising findings for people with Alzheimer’s who are on SSRIs. Our results demonstrate how specific types of this medication can prevent amyloid-beta aggregation, and thus delay the development of dementia in patients diagnosed with mild cognitive impairment and Alzheimer’s,” said Nekkar.
Though further testing is required, this knowledge can one day inform how health care providers approach treatment in patients with both depression and Alzheimer’s. For example, if a patient is diagnosed with depression and has a family history of Alzheimer’s, they can be started on SSRIs early.
“Our results can also inform future drug development,” said Nekkar. “The chemical structure of SSRIs presents a type of blueprint for how to develop medication that will prevent amyloid beta aggregation. We can explore developing new drugs based on that model to treat Alzheimer’s.”
Nekkar’s study recently appeared in journal ACS Chemical Neuroscience.