Lady Davis Institute

Through a series of studies, Dr. Andréa LeBlanc, a principal investigator at the Lady Davis Institute at the Jewish General Hospital, has discovered elevated levels of the protein Caspase-6 in the area of the brain – namely, the hippocampus, which is responsible for memory and cognition – first damaged by Alzheimer’s disease. This phenomenon is seen from the very earliest stages of cognitive impairment.

Dr. LeBlanc has demonstrated for the first time in a mouse model that Caspase-6 activity, in the absence of the plaques and tangles that are also abundant in the brain of Alzheimer’s sufferers, is responsible for memory deficits and impaired cognitive function comparable to that which afflicts humans. Her findings were published in Cell Death & Differentiation.
“Caspase-6 is highly abundant in every Alzheimer’s afflicted brain that we have studied, and we have found a correlation between higher amounts of active Caspase-6 and lower cognitive function in aged individuals, particularly in episodic memory, which one of the first types of memory to decline in Alzheimer’ disease,” said Dr. LeBlanc, who is also James McGill Professor of Neurology and Neurosurgery at McGill University.
It has been her hypothesis that the amyloid plaques that characterize a brain ravaged by Alzheimer’s are likely a late symptom of the disease, as opposed to an early cause. By creating a mouse model that expresses Caspase-6 in the area of the brain responsible for memory and ascertaining that the animal experiences memory loss in the absence of plaques of tangles, she has put forth a strong case that Caspase-6 is a probable causal factor for Alzheimer’s cognitive impairment.
“The mouse model proves that Caspase-6 activity is sufficient to cause cognitive impairment,” she said. “Moreover, it evolves as an age-related feature, which mirrors the development of Alzheimer’s in humans.”
While under normal circumstances there is very little Caspase-6 in the brain, large amounts are associated with classical Alzheimer Disease pathology and Caspase-6 is now well accepted to cause neuronal degeneration in a variety of laboratory conditions . A question still to be explored is why Caspase-6 accumulates in a cognitively impaired brain.
Future research objectives include identifying and testing Caspase-6 inhibitors in order to develop a therapy that may prevent the progression of Alzheimer’s in aging individuals. This new Caspase-6 mouse model is essential for early pre-clinical trials.
“We’re looking at novel inhibitors that we hope will prove to be effective,” she explains. “A good inhibitor needs to be very selective, in that it can only target Caspase-6, it must also be non-toxic, and be delivered to the brain efficiently.”







January 10, 2014