Grant: Project Grant

More than 740,000 Canadians are living with Alzheimer disease (AD) or related dementia, a number expected to double by 2031. Compared to other prevalent diseases, the absence of effective treatments for AD is shocking. It is of prime importance for AD patients, their loved ones and the society as a whole, that we rapidly develop new therapeutic strategies. To achieve that aim, the identification of new relevant drug targets is the key. My laboratory has always been trying to understand why neurons fail to communicate in AD and whether it is caused by loss of proteins located in "synapses", where neurons interconnect with each other. My specific interest in one of those synapse proteins, Shank3, started when I learned 5 years ago that the child of one of my close friend had mental retardation due to a lack of this protein. I could witness with my own eyes the consequence of a loss of 50% of this protein on a child's capacity to learn and memorize. If lacking Shank3 has such an effect on a child, could it do the same in AD? We then found that there is almost 50% less Shank3 in the brain of AD patients. Since we know that children born missing 50% of the gene coding for Shank3 display extensive cognitive impairments, it seems likely that a comparable loss of Shank3 protein in AD may contribute to symptoms. To test that hypothesis, we thus propose to determine whether the consequences of shutting down half of Shank3 in animal models leads to signs and symptoms similar to AD. In summary, the proposed experiments in animal models will establish whether (i) Shank3 deactivation causes or aggravates behavioral, functional and biochemical markers of AD, (ii) it is possible with 3 selected treatments to reverse the deleterious effects of a Shank3 loss. The ultimate goal is to find out whether Shank3 could be a suitable target to develop new treatments for AD.