Study leads to potential new drug treatment for early stages of disease

E. Wilson TSCovertly, Alzheimer’s disease progresses silently over decades in those afflicted before symptoms appear, during which time memory impairments are often masked. During this early period of the onset of the disease, one can, either consciously or unconsciously, make use of strategies to hide a memory problem. For instance, imagine someone rehearsing a word’s definition out loud over and over again to help them remember it. Or someone using a mnemonic to help navigate their route home from the office based on street names: “To get home, I remember CAMPS: I must turn on Cottage St., then Aigle St, Martin St., Prince St., and then finally onto Silver Birch Dr.” Compensation mechanisms like these make it difficult to get a proper diagnosis, early in the disease’s progression, when Alzheimer’s drugs have the best chances of being effective and have made it impossible to study the early stages of the disease in humans.

Now, in a study published recently in the journal Cerebral Cortex, researchers at McGill University made an important breakthrough in identifying the protein responsible for memory loss in these early stages of Alzheimer’s disease.

Using rat models

To conduct their study, researchers in the lab of Dr. Claudio Cuello, Professor in the Department of Pharmacology and Therapeutics at McGill’s Faculty of Medicine worked with researchers in the lab of Dr. Yogita Chudasama, now at the National Institutes of Health, using transgenic rats for their subjects as their brains are much closer to the human brain than those of the traditional transgenic mice models.

“We thought that a sophisticated cognitive test that prevented such compensation could allow us to better detect subtle memory loss at the very early stages of the disease,” says Edward Wilson, a PhD candidate in Dr. Cuello’s lab and lead author on the paper.  “This could lead us to the early cellular changes underlying the disease.”

When they tested the McGill Alzheimer rats using an advanced touchscreen-based testing system, it was immediately obvious to the researchers that these rats were impaired. The researchers found striking deficits in the Alzheimer rats. They made many errors and couldn’t learn the task, and they were slower to make decisions and to collect rewards, while the healthy rats could do these things very easily.

Further investigation identifies protein and potential treatment

To investigate these defects further, the researchers delved into the hippocampus, where they found that the Alzheimer rats showed impairment in cellular signaling needed to build new memories and to keep old ones intact. Messages were prevented from reaching the nucleus, which controls protein expression. They found that the protein CRTC1 had an impairment moving from the cytoplasm to the cell nucleus in neurons. The outcome of such impairment was a loss of gene expression required for memory. The researchers concluded that this deficit suggests that similar impairments in synaptic plasticity should occur in humans in the course of Alzheimer’s disease that contributes to memory loss.

“These results indicate that novel drugs facilitating the expression and function of the CRTC1 protein should ameliorate the negative consequences of its failure in cognitive mechanisms in the early Alzheimer’s pathology,” says Dr. Cuello. “Such a strategy could offer as a potential therapeutic target for treating early phases of Alzheimer’s disease.”

This study was made possible with funding from the Canadian Institutes of Health Research, the Centres of Excellence in Neurodegeneration, Dr. A. Frosst, the Frosst family, and Merck Canada.

February 4, 2016