Harnessing beneficial aspects of neuroinflammation for regenerating the central nervous system
Principal Investigator: Dr. V. Wee Yong, University of Calgary
Team members: Dr. Luanne Metz, University of Calgary
Dr. Christopher Power, University of Alberta
Dr. Peter Stys, University of Calgary
Dr. Fiona Costello, University of Calgary
Dr. Serge Rivest, Université Laval.
This research project, led by Dr. V. Wee Yong from the University of Calgary, focused on the immune system, which is comprised of two major components, the innate and adaptive systems. Innate immunity is the first immune component to sense and respond to an injury. Indeed, a well-regulated innate immune response is a normal physiological process that is essential for functions such as wound healing and defense against foreign substances. Within the central nervous system (CNS), microglia are the resident cell population belonging to the innate immune system. Under conditions of CNS injury, another innate immune cell type, the macrophage, accesses the brain and spinal cord. The initial emphasis was on the role that such activated innate immune cells play in promoting the disease process in conditions such as stroke, multiple sclerosis and spinal cord injury. Only more recently is there attention on the contribution of the innate immune system in improving the well being of the CNS. Indeed, this research team postulated that a well-regulated immune reactivity in the CNS can enable repair of the nervous system.
They sought to define the conditions under which physiologic neuroinflammation enables recovery, and to harness the beneficial aspects of innate neuroinflammation to allow the regeneration of the CNS from insults. This approach is transformational, as it promises to deliver new means to enabling CNS regeneration. These experiments are relevant to promoting recovery from several neurological disorders, including stroke, Multiple Sclerosis, spinal cord injury, and Alzheimer’s disease.
Dr. Yong and his team have made significant progress. Using worldwide MS prevalence data and assessing 11 risk factors, they have found that the lack of ultraviolet B radiation (and the corresponding deficiency of vitamin D) is the single most important risk factor for the development of MS.
They have extended the knowledge of the immunologic mechanisms by which vitamin D improves wellbeing in MS and have uncovered new insights into vitamin D: that vitamin D is a protective agent against injury to axons and neurons
The team has also uncovered potential new medications for MS and other neurological conditions: crocin, dipyridamole and atipamezole. The last is very interesting because it uniquely acts on neurons to increase their defense mechanisms, even when there is widespread inflammation
In human MS patients, measurements of the optic nerve using optical coherence tomography (OCT) provide evidence for the continued loss of axons in MS, and that the rate differs across the subgroups of MS. Dr. Yong’s team are now enrolling MS patients for a pilot trial of neuroprotection by minocycline in MS using the optic nerve and OCT as models.
The team has also continued to refine the discovery that amphotericin B, an anti-fungal agent, activates microglia/macrophage, and that amphotericin B can be used safely in mice to promote recovery from a demyelinating injury. This could represent a new means to promote repair from demyelinating conditions in humans. By stimulating microglia with M-CSF, they have found that this promotes clearance of Aβ toxic deposits in the brain of mice with Alzheimer disease pathology. Remarkably, once weekly M-CSF treatment is effective in halting progression of Alzheimer symptoms in mice, even when treatment is initiated late in disease when amyloid plaques are already well entrenched