BACKGROUND
Nutrition plays a central role in brain function and cognition at all stages of life. Historically
discovered for its role in blood coagulation, there is now convincing evidence that VK has
important actions in the nervous system. As a unique cofactor to the γ-glutamyl carboxylase
enzyme, VK contributes to the biological activation of proteins S and Gas6 involved in cellular
processes such as cell growth, survival and apoptosis. In the nervous system, VK also participates in
the synthesis of sphingolipids, a class of structural lipids found in high concentrations in brain cell
membranes which also possess important cell signaling activities. Functionally, these lipids have
been associated with cell proliferation, differentiation, senescence and transformation. Although
limited in numbers, reports also point to a role for VK in cognition. As detailed later, our group has
contributed significant data to this emerging function, providing evidence that VK deficiency,
whether diet- or warfarin-induced, results in cognitive deficits. Finally, there is growing evidence
that the K vitamer, menaquinone-4 (MK-4) has anti-inflammatory activity and offers protection
against oxidative stress.
Although a role for VK in brain function is no longer disputed, most of our current
knowledge about its actions at the cellular level has been obtained as part of in vitro studies.
Notewhistanding their groundbreaking value, there is now an urgent need to conduct in vivo studies
to characterize the actions of the vitamin in more physiological conditions. Until solid data is
obtained using animal models, the reported actions for VK in the nervous system will remain
elusive. This application addresses this issue directly by proposing mechanistic and translational
studies using two rodent models which have been shown to be responsive to VK status.
RESEARCH AIMS
Building on previous work from our team, we propose to conduct studies aimed at
obtaining essential mechanistic information regarding the actions of VK at the cellular level
and at determining whether VK-induced cognitive deficits can be reversed by restoration of
status through diet. Our mechanistic studies will focus on neuronal cell survival, the inflammatory
process and, cell signaling. Our behavioural studies will significantly expand our previous work and
will include yet un-investigated cognitive domains such as executive function. This is important as,
executive function along with memory, is the cognitive domain most affected during aging.
IMPACT OF THE RESEARCH
The proposed research programme will contribute milestone knowledge on the role of VK in
brain function in vivo and will guide future research endavours including intervention studies in
humans. Recent nutritional surveys, including data from a canadian sub-group, point to low VK
intake and suboptimal VK status in the general population. Also, individuals on warfarin therapy
(Coumadin) are by definition in a chronic state of VK deficiency as this drug blocks the recycling
of the vitamin. The translational potential of the present research programme is hence very high and
could, ultimately, influence nutritional recommendations for VK. Currently, dietary
recommendations for VK in North America, the United Kingdom, and the WHO/FAO are based on
its role in blood clotting. As pointed out in the Dietary Reference Intake Report on Micronutrients,
«...research needs to be pursued to further our knowledge of the health role of vitamin K outside of
Gla synthesis... ». This research programme directly addesses this recommendation in addition to
contributing important knowledge on the potential detrimental effect of the use of the widelyprescribed
oral anticoagulant, warfarin.